Cd73 inhibitors

ABSTRACT

Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/760,380, filed Apr. 29, 2020, which is a § 371 U.S. National StageEntry of International Application No. PCT/US2018/059004, filed Nov. 2,2018, which claims the benefit of U.S. Provisional Application No.62/581,574, filed Nov. 3, 2017, and U.S. Provisional Application No.62/664,841, filed Apr. 30, 2018, which are all hereby incorporated byreference in their entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer,infections, and neurodegenerative diseases.

BRIEF SUMMARY OF THE INVENTION

Provided herein are compounds of Formulas (I), (II), (IIa), (IIb),(III), and (IV) or pharmaceutically acceptable salts, solvates, orstereoisomers thereof, and pharmaceutical compositions comprising saidcompounds. The subject compounds and compositions are useful as CD73inhibitors. Furthermore, the subject compounds and compositions areuseful for the treatment of cancers, infections, and neurodegenerativediseases.

Provided herein are compounds having the structure of Formula (Ita), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein;

-   -   A is —O— or —CH₂—;    -   Q¹ is CW and Q² is N; or    -   Q¹ is N and Q² is N;    -   W is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),        —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(O)₂R⁸, —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d),        —NR^(b)C(═O)R^(a), —NR^(b)C(C₁-C₆alkyl, C₁-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(O)₂R^(15a),        —S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)+R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR¹⁶R, —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16c)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   X¹ is a bond;    -   Y¹ is —S(═O)₂—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—;    -   R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v2 is 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g),        R^(17a), R^(17b), R^(17c), R^(17f), and R^(17g) are each        independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₄ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²³,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²S; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂₋₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30g),        R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m), R^(30n),        and R^(30o) are independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)RR,        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O) R^(b), C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

Also provided herein are compounds having the structure of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof:

wherein;

-   -   Q³ and Q⁴ are independently N or CW¹; provided that at least one        of Q³ or Q⁴ is N;    -   W¹ is hydrogen, halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   A is —O— or —CH₂—:

Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;

-   -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(O)₂R^(15a),        —S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)+R^(15g), —NHS(═O)₂R^(15g),        —S(O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(16g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, —O—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —C(═O)—, —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, —S—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30p);    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or        heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30f);    -   v1 and v2 are each independently 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g),        R^(17a), R^(17b), R^(17e), R^(17g), and R^(17g) are each        independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(O)OR²⁵,        —(CR²³R²⁴)_(w)OC(O)R²⁶, —(CR¹³R²⁴)_(w)SC(═O)R²⁵, or        —(CR¹³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m),        R^(30n), R^(30o), and R^(30p) are independently halogen, —CN,        —OH, —OR^(a), —SH, —SR^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH.        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

Also disclosed herein are pharmaceutical compositions comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, and a pharmaceutically acceptableexcipient.

Also disclosed herein are methods of inhibiting CD73 comprisingcontacting CD73 with a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof.

Also disclosed herein are methods of treating cancer in a subject,comprising administering to the subject a compound disclosed herein, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof oradministering to the subject a pharmaceutical composition comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, and a pharmaceutically acceptableexcipient.

Also disclosed herein are methods of treating an infection in a subject,comprising administering to the subject a compound disclosed herein, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof oradministering to the subject a pharmaceutical composition comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, and a pharmaceutically acceptableexcipient.

Also disclosed herein are methods of treating a neurodegenerativedisease in a subject, comprising administering to the subject a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof or administering to the subject a pharmaceuticalcomposition comprising a compound disclosed herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, anda pharmaceutically acceptable excipient.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surfaceprotein that catalyzes the hydrolysis of AMP to adenosine, and works inconcert with CD39, which converts ATP into AMP. The resulting adenosinefunctions as a signaling molecule that activates the P1 receptorsexpressed on the cell surface in many different tissues. Four Gprotein-coupled P1 or adenosine receptors have been cloned anddesignated as A1, A2A, A2B, and A3. Adenosine impacts a wide range ofphysiological processes including neural function, vascular perfusion,and immune responses. In doing so, this metabolite regulates CNS,cardiovascular, and immune system functions, to name a few.

Increasing evidence suggests that interactions between tumor cells andtheir microenvironment are essential for tumorigenesis. The purinergicsignaling pathway in which CD73 plays a critical role, has emerged as animportant player in cancer progression. It has become clear in recentyears that adenosine is one of the most important immunosuppressiveregulatory molecules in the tumor microenvironment, and contributes toimmune escape and tumor progression.

CD73 is a key protein molecule in cancer development. CD73 has beenfound to be overexpressed in many cancer cell lines and tumor typesincluding, for example, breast cancer, colorectal cancer, ovariancancer, gastric cancer, gallbladder cancer, and cancers associated withpoor prognosis.

The expression of CD73 in tumors is regulated by a variety ofmechanisms. CD73 expression is negatively regulated by estrogen receptor(ER) in breast cancer. Thus. CD73 is highly expressed in ER negativebreast cancer patients. The hypoxia-inducible factor-1α (HIF-1α) hasalso been shown to regulate CD73 transcription. Additionally,inflammatory factors such as IFN-γ affect CD73 levels. CD73 expressionis also epigenetically regulated by CpG island methylation in cell linesand clinical tumor samples.

In addition to being a prognostic biomarker in cancer patients,overexpression of CD73 has also been found to be functionally linked totherapy resistance. Elevated levels of CD73 were initially linked toresistance to a variety of chemotherapeutic agents including vincristineand doxorubicin.

CD73 has also been shown to be involved in immunotherapy resistance.This ectonucleotidase participates in the process of tumor immune escapeby inhibiting the activation, clonal expansion, and homing oftumor-specific T cells (in particular, T helper and cytotoxic T cells):impairing tumor cell killing by cytolytic effector T lymphocytes;driving, via pericellular generation of adenosine, the suppressivecapabilities of Treg and Th 17 cells; enhancing the conversion of type 1macrophages into tumor-promoting type 2 macrophages; and promoting theaccumulation of MDSCs.

Small molecular inhibitors and monoclonal antibodies targeting CD73 haveshown anti-tumor activity in a variety of immune-competent but not inimmune-deficient mouse tumor models. Overall, these studies suggest thatanti-CD73 therapy activity is dependent on its ability to elicit immuneresponses in vivo.

Antibodies which block PD-1, PD-L1, and CTLA-4 have shown impressiveobjective response in cancer patients. Recent data demonstrates thatanti-CD73 mAb significantly enhances the activity of both anti-CTLA-4and anti-PD-1 mAbs in several mouse tumor models. In addition tocheckpoint blockade, CD73-mediated production of adenosine couldcontribute to resistance to additional immunotherapy modalitiesincluding CAR-T cells and cancer vaccines.

Interfering with CD73 activity represents a strategy to re-sensitizetumors to therapy. Based on the link between CD73 and therapyresistance, combining anti-CD73 treatment with chemotherapy orimmunotherapy is an effective approach to enhance their activity incancer patients with high CD73 levels. In some instances, CD73expression serves as a biomarker to identify patients that could benefitfrom anti-CD73 combination therapy.

In some instances, the CD39/CD73 couple turns ATP-drivenpro-inflammatory cell activity toward an adenosine-mediatedanti-inflammatory state. A number of studies have shown changes in theactivity of the CD39/CD73 axis during infections induced by a variety ofmicroorganisms. An increase in CD73 expression has also been observed inthe brain of mice infected with Toxoplasma gondii, which promotes theparasite life cycle through the production of adenosine. Thus, thepharmacological blockade of CD73 is a promising therapeutic approach totreat human toxoplasmosis.

Enhanced expression and activity of CD39 and CD73 have been observed inendothelial cells infected with cytomegalovirus (CMV). The increase inlocal adenosine production, associated with the upregulation ofecto-nucleotidases, generates an immunosuppressive and antithromboticmicroenvironment, which facilitates viral entry into target cells.

In some instances, inhibitors of CD73, by driving a decrease onadenosine production, have applications as antiviral agents. Theelevated expression/activity of CD39 and CD73 on lymphocytes ofindividuals infected with human immunodeficiency virus (HIV) indicates arole for ecto-nucleotidases in the immune dysfunction associated withthis disease. In fact, an increased proportion of Tregs expressing CD39,as well as a positive correlation between CD39 expression on Tregs anddisease progression has been observed in different cohorts ofHIV-infected patients. It has also been shown that HIV-positive patientshad a higher number of CD39+ Treg, and that their Teff exhibited anincreased sensitivity in vitro to the suppressive effect of adenosine,which was related to the elevated expression of immunosuppressive A2Areceptors.

In the central nervous system, adenosine plays a critical role incontrolling a multitude of neural functions. Through the activation ofP1 receptors, adenosine is involved in diverse physiological andpathological processes such as regulation of sleep, general arousalstate and activity, local neuronal excitability, and coupling of thecerebral blood flow to the energy demand. In some instances,manipulation of adenosine production via CD73 inhibitors is useful fortreating neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and Huntington's disease, and psychiatric disorderssuch as schizophrenia and autism.

Definitions

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, or from one to six carbonatoms, wherein a sp3-hybridized carbon of the alkyl residue is attachedto the rest of the molecule by a single bond. Examples include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, suchas heptyl, octyl, and the like. Whenever it appears herein, a numericalrange such as “C₁-C₆ alkyl” means that the alkyl group consists of 1carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbonatoms or 6 carbon atoms, although the present definition also covers theoccurrence of the term “alkyl” where no numerical range is designated.In some embodiments, the alkyl is a C₁-C₁₀alkyl, a C₁-C₉ alkyl, a C₁-C₈alkyl, a C₁-C₇ alkyl, a C₁-C₆ alkyl, a C₁-C₅alkyl, a C₁-C₄ alkyl, aC₁-C₃ alkyl, a C₁-C₂ alkyl, or a C₁ alkyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, the alkyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, the alkyl is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, or —OMe. In some embodiments, the alkyl is optionallysubstituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms, wherein ansp2-hybridized carbon of the alkenyl residue is attached to the rest ofthe molecule by a single bond. The group may be in either the cis ortrans conformation about the double bond(s), and should be understood toinclude both isomers. Examples include, but are not limited to ethenyl(—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)═CH₂], butenyl,1,3-butadienyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” means that the alkenyl group may consistof 2 carbon atoms. 3 carbon atoms. 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrenceof the term “alkenyl” where no numerical range is designated. In someembodiments, the alkenyl is a C₂-C₁₀ alkenyl, a C₂-C₉ alkenyl, a C₂-C₈alkenyl, a C₂-C₇ alkenyl, a C₂-C₆ alkenyl, a C₂-C₅ alkenyl, a C₂-C₄alkenyl, a C₂-C₃ alkenyl, or a C₂ alkenyl. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, an alkenyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, an alkenyl is optionally substituted with oxo,halogen, —CN, —CF₃, —OH, or —OMe. In some embodiments, the alkenyl isoptionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms.Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl,1,3-butadiynyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkynyl” means that the alkynyl group may consistof 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrenceof the term “alkynyl” where no numerical range is designated. In someembodiments, the alkynyl is a C₂-C₁₀ alkynyl, a C₂-C₉ alkynyl, a C₂-C₈alkynyl, a C₂-C₇ alkynyl, a C₂-C₆ alkynyl, a C₂-C₅ alkynyl, a C₂-C₄alkynyl, a C₂-C₃ alkynyl, or a C₂ alkynyl. Unless stated otherwisespecifically in the specification, an alkynyl group is optionallysubstituted for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, an alkynyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or NO₂. Insome embodiments, an alkynyl is optionally substituted with oxo,halogen, —CN, —CF₃, —OH, or —OMe. In some embodiments, the alkynyl isoptionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain.Unless stated otherwise specifically in the specification, an alkylenegroup may be optionally substituted for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, analkylene is optionally substituted with oxo, halogen, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an alkylene is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. In someembodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —OR, where IL is an alkylradical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, an alkoxy is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, an alkoxy isoptionally substituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the alkoxy is optionally substituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with acycloalkyl or heterocycloalkyl ring, the aryl is bonded through anaromatic ring atom) or bridged ring systems. In some embodiments, thearyl is a 6- to 10-membered aryl. In some embodiments, the aryl is a6-membered aryl. Aryl radicals include, but are not limited to, arylradicals derived from the hydrocarbon ring systems of anthrylene,naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene,fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. In some embodiments, the aryl is phenyl. Unless statedotherwise specifically in the specification, an aryl may be optionallysubstituted for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, an arylis optionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an aryl is optionallysubstituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a stable, partially or fully saturated,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocyclesinclude, for example, adamantyl, norbomyl, decalinyl,bicyclo[3.3.6]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkylsinclude, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Unless stated otherwise specifically in the specification,a cycloalkyl is optionally substituted for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, a cycloalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, a cycloalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, thecycloalkyl is optionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, di fluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoroamyl,1,2-dibromoethyl, and the like.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially orfully saturated ring radical comprising 2 to 23 carbon atoms and fromone to 8 heteroatoms selected from the group consisting of nitrogen,oxygen, phosphorous and sulfur. Unless stated otherwise specifically inthe specification, the heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fused(when fused with an aryl or a heteroaryl ring, the heterocycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems; andthe nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical maybe optionally oxidized; the nitrogen atom may be optionally quaternized.In some embodiments, the heterocycloalkyl is a 3- to 6-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicalsinclude, but are not limited to, aziridinyl, azetidinyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoinddyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4 yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. Unlessotherwise noted, heterocycloalkyls have from 2 to 10 carbons in thering. It is understood that when referring to the number of carbon atomsin a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring). Unless stated otherwise specifically inthe specification, a heterocycloalkyl is optionally substituted forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,or —OMe. In some embodiments, the heterocycloalkyl is optionallysubstituted with halogen.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atomsand one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.—NH—, —N(alkyl)-), sulfur, or combinations thereof wherein theheteroalkyl is attached to the rest of the molecule at a carbon atom ofthe heteroalkyl. Unless stated otherwise specifically in thespecification, a heteroalkyl is optionally substituted for example, withoxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, andthe like. In some embodiments, a heteroalkyl is optionally substitutedwith oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂.In some embodiments, a heteroalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments,the heteroalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. The heteroarylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused (when fused with a cycloalkyl orheterocycloalkyl ring, the heteroaryl is bonded through an aromatic ringatom) or bridged ring systems; and the nitrogen, carbon or sulfur atomsin the heteroaryl radical may be optionally oxidized: the nitrogen atommay be optionally quaternized. In some embodiments, the heteroaryl is a5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a5- to 6-membered heteroaryl. Examples include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quindinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl is optionallysubstituted for example, with halogen, amino, nitrite, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, aheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, a heteroaryl isoptionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or—OMe. In some embodiments, the heteroaryl is optionally substituted withhalogen.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more —OH e.g., hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl, hydroxypentyl, dihydroxymethyl,dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, andthe like.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,010 daltons, and more typically, up to about 500daltons.

The terms “inhibit,” “block,” “suppress,” and grammatical variantsthereof are used interchangeably herein and refer to any statisticallysignificant decrease in biological activity, including full blocking ofthe activity. In some embodiments, “inhibition” refers to a decrease ofabout 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 90% or about 100% in biological activity.Accordingly, when the terms “inhibition” or “suppression” are applied todescribe, e.g., an effect on the enzymatic activity of CD73, the termrefers to the ability of a compound disclosed herein to statisticallysignificantly decrease the 5′-nucleotidase activity of CD73(catabolizing the hydrolysis of adenosine monophosphate, AMP, toadenosine), relative to the CD73-mediated 5′-nucleotidase activity in anuntreated (control) cell. In some instances, the cell which expressesCD73 is a naturally occurring cell or cell line (e.g., a cancer cell) oris recombinantly produced by introducing a nucleic acid encoding CD73into a host cell. In some aspects, compounds disclosed hereinstatistically significantly decrease the 5′-nucleotidase activity of asoluble form of CD73 in a biological fluid. In one aspect, the compounddisclosed herein inhibit CD73-mediated 5′-nucleotidase activity by atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or about 100%, as determined, forexample, by the methods described in the Examples and/or methods knownin the art.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

Compounds

Described herein are compounds that are CD73 inhibitors. Thesecompounds, and compositions comprising these compounds, are useful forthe treatment of cancer, infections, and neurodegenerative diseases.

In some embodiments provided herein is a compound having the structureof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof:

wherein;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, alkyl, alkenyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl),        —S(O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a) or —C(═O)₂R^(15a); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three        R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl),        or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30d);

R⁵ and R⁶ are each independently hydrogen, halogen, —OH, —OR^(15d),—NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30e);

-   -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), alkyl, or        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, alkyl, or        haloalkyl;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(O)R^(a),        —S(O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30f);    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), alkyl, or haloalkyl;    -   v is 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g),        R^(17a), R^(17b), R^(17c), R^(17d), R^(17e), R^(17f), and        R^(17g) are each independently hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30b);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, alkyl, or haloalkyl;    -   R^(18b) is alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²⁰ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl),        alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   R²¹ and R²² are each independently hydrogen, alkyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), alkyl, or haloalkyl;    -   each R²⁵ is independently hydrogen, alkyl, alkenyl, alkynyl, or        heteroalkyl;    -   each R²⁶ is independently alkyl, alkenyl, alkynyl, or        heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m),        R^(30n), and R^(30o) is independently halogen, —CN, —OH,        —OR^(a), —SH, —SR^(a), —S(O)R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(O)OR^(b), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), alkyl, haloalkyl, hydroxyalkyl, heteroalkyl,        or cycloalkyl optionally substituted with one, two, or three        halogen, alkyl, or haloalkyl; each R^(a) is independently alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        halogen, —OH, alkyl, or haloalkyl;    -   each R^(b) is independently hydrogen, alkyl, alkenyl, alkynyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three halogen, —OH,        alkyl, or haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, alkyl, alkenyl,        alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        halogen, —OH, alkyl, or haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, alkyl, or        haloalkyl.

In some embodiments provided herein is a compound having the structureof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof wherein;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(O)OR^(b), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or —C(O)R^(15a); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or        heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30f);    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v is 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), and        R^(15g) are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g),        R^(17a), R^(17b), R^(17c), R^(17d), R^(17e), R^(17f), and        R^(17g) are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl        is independently optionally substituted with one, two, or three        R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(O)OR; wherein each        alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30j);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)R²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m),        R^(30n) and R^(30o) is independently halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁₋₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optimally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, when X is —O—, Y isnot —CH₂—, —CCl₂—, —CF₂—, or —C(CH₃)₂—. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X is —NR¹¹—. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X is —NR¹¹— and R¹¹ is hydrogen or alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, v is 2 or 3. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —NR¹²—.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a). —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   v is 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)CO(═O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30j);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30j), R^(30k), and R^(30l) is        independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),        —C(═O)R^(a), —C(O)OR^(b), —C(O)NR^(c)R^(d), C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   provided that, when X is —O—, Y is not —CH₂—, —CCl₂—, —CF₂—, or        —C(CH₃)₂—.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen or C₁-C₆ alkyl;    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, or C₁-C₆        alkyl;    -   v is 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²⁰ is hydrogen, C₁-C₂₀alkyl, —(CR²³R²⁴)_(w)OC(O)OR²⁵, or aryl        optionally substituted with one, two, or three R^(30j);    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(n)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30l);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30j), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl; and    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl;    -   provided that, when X is —O—, Y is not —CH₂—, —CCl₂—, —CF₂—, or        —C(CH₃)₂—.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optimally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X is —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   v is 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30f);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30j);    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR¹³; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30j);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²³; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), and R^(30l) is        independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₄ heteroalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X is —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen or C₁-C₆ alkyl;    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, or C₁-C₆        alkyl;    -   v is 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl        optionally substituted with one, two, or three R^(30j);    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30k);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30j), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl; and    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl. C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, my, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(13c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴), or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R¹³ and R¹⁴ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   v is 2 or 3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30j);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴) C(═O)OR²⁵,        —(CR¹³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), and R^(30l) is        independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),        —C(O)R^(a), —C(═O)OR^(b), —C(O)NR^(c)R^(d), C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X is —O— or —NR¹¹—;    -   Y is —(CR¹³R¹⁴)_(v)— or —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen or C₁-C₆ alkyl;

R¹³ and R¹⁴ are each independently hydrogen, halogen, or C₁-C₆ alkyl;

-   -   v is 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl        optionally substituted with one, two, or three R^(30j);    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30j), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl; and    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(O)R^(13c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X is —O— or —NR¹¹—;    -   Y is —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30b);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, cycloalkyl, heterocycloalkyl,        aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30j);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂—Co alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), and R^(30l) is        independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X is —O— or —NR¹¹—;    -   Y is —NR¹²—;    -   R¹¹ and R¹² are each independently hydrogen or C₁-C₆ alkyl;    -   R^(15c) is C₁-C₆ alkyl;    -   R²⁰ is hydrogen, C₁-C₂₀ alkyl, —(CR²³R²⁴)_(w)OC(O)OR²⁵, or aryl        optionally substituted with one, two, or three R^(30j);    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²³, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30j), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl; and    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl.        For any and all of the embodiments of Formula (I), substituents        are selected from among a subset of the listed alternatives.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁸ is hydrogen,halogen, —OH, —OMe, —NH₂, —NH(CH₃), —N(CH₃)₂, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁸is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁸ is hydrogen,halogen, —OH, —NH₂, or C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R₈ is hydrogen or C₁-C₆ alkyl. In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁸ is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁹ and R¹⁰ are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁹ and R¹⁰ are each hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Q¹ is N; and Q² isCW. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is CW; and Q² is N. In some embodiments of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is N; and Q² is N. In some embodiments of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is CW; and Q² is CW.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —CN, —OH, —OR, —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰; andeach R³⁰ is independently halogen or C₁-C₆alkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each W is independently hydrogen,halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, A is —O—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, A is —CH₂—.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —O—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —NR¹¹—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —NR¹¹—; and R¹¹is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, X is —NR¹¹—; and R¹¹ is hydrogen or methyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —NR¹²—. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —NR¹²—; and R¹²is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, Y is —NR¹²—; and R¹² is hydrogen or methyl. In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, Y is —NR¹²—; and R¹² is hydrogen. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —NR¹²—; and R¹²is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—.In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each independently hydrogen, halogen, or C₁-C₆ alkyl;and v is 1 or 2. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is—(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are each independently hydrogen, halogen,or C₁-C₆ alkyl; and v is 2 or 3. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are eachindependently hydrogen, halogen, or C₁-C₆ alkyl; and v is 1. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each independently hydrogen, halogen, or C₁-C₆ alkyl;and v is 2. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is—(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are each hydrogen; and v is 1 or 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each hydrogen; and v is 2 or 3. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are eachhydrogen; and v is 1. In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are each hydrogen; and v is 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each halogen or C₁-C₆ alkyl; and v is 1 or 2. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each halogen or C₁-C₆ alkyl; and v is 2 or 3. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each halogen or C₁-C₆ alkyl; and v is 1. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y is —(CR¹³R¹⁴)_(v)—;R¹³ and R¹⁴ are each halogen or C₁-C₆ alkyl; and v is 2.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —O— and Y is—NR¹²—. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—O—; Y is —NR¹¹—; and R¹² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is—NR¹²—; and R¹² is hydrogen. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X is —O—; Y is —NR¹²—; and R¹² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —NR¹¹— and Y is—(CR¹³R¹⁴)_(v)—. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—NR¹¹—; Y is —(CR¹³R¹⁴)_(v)—; R¹¹ is hydrogen or C₁-C₆ alkyl; R¹³ andR¹⁴ are each independently hydrogen, halogen, or C₁-C₆ alkyl; and v is 1or 2. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—NR¹¹—; Y is —(CR¹³R¹⁴)_(v)—; R¹¹ is hydrogen; R¹³ and R¹⁴ are eachhydrogen; and v is 1. In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X is —NR¹¹—; Y is —(CR¹³R¹⁴)_(v)—; R¹¹ is C₁-C₆ alkyl; R¹³ and R¹⁴ areeach hydrogen; and v is 1.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —NR¹¹— and Y is—NR¹²—. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—NR¹¹—; Y is —NR¹¹—; R¹¹ is hydrogen or C₁-C₆ alkyl; and R¹² is hydrogenor C₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—NR¹¹—; Y is —NR¹²—; R¹¹ is hydrogen; and R¹² is hydrogen. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —NR¹¹—; Y is—NR¹²—; R¹¹ is C₁-C₆ alkyl; and R¹² is C₁-C₆ alkyl. In some embodimentsof a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, X is —NR¹¹—; Y is —NR¹²—; R¹¹ ishydrogen; and R¹² is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X is —NR¹¹—; Y is —NR¹²—; R¹¹ is C₁-C₆ alkyl; andR¹² is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is—(CR¹³R¹⁴)_(v)—. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is—O—; Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are each independently hydrogen,halogen, or C₁-C₆alkyl; and v is 2 or 3. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X is —O—; Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ areeach hydrogen; and v is 2. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, X is —O—; Y is —(CR¹³R¹⁴)_(v)—; R¹³ and R¹⁴ are each hydrogen;and v is 3.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁵ and R⁶ are eachindependently hydrogen, halogen, C₁-C₆ alkyl, or cycloalkyl; whereineach alkyl and cycloalkyl is independently optionally substituted withone, two, or three R^(30e). In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e); and each R^(30e)is independently halogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁵ and R⁶ are each hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are eachindependently hydrogen, halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c),—NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30d). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen, —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30d); and each R^(30d) isindependently halogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁴ and R⁷ are each independently hydrogen,halogen, —OH, —OR^(15c). —NR^(16c)S(═O)₂R^(15c), or—NR^(16c)C(O)R^(15c). In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁴ and R⁷ are each independently hydrogen, halogen. —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), or —NR^(16c)C(═O)R^(15c); R^(15c) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl; and R^(16c) are eachindependently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are eachindependently hydrogen, halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c),or —NR^(16c)C(═O)R^(15c); R^(15c) are each independently C₁-C₆ alkyl;and R^(16c) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are eachindependently hydrogen, halogen, or —OH. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁴ and R⁷ are each independently halogen or—OH. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof: R⁴and R⁷ are each —OH.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Z is —NR¹R².

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30a). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30a); R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl (aryl);wherein each alkyl and aryl is optionally substituted with one, two, orthree halogen; and R^(16a) and R^(17a) are each independently hydrogen,C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(O)R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30a); R^(15a) is C₁-C₆ alkyl; and R^(16a) and R^(17a) are eachindependently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15a) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16a) andR^(17a) are each independently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15a) is C₁-C₆ alkyl; and R^(16a) and R^(17a) are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15a) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(16a) and R^(17a) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(16a) and R^(17a)are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆ alkyl,cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆ alkyl,cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, andaryl is independently optionally substituted with one, two, or threeR^(30a). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof: R¹is cycloalkyl or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, andaryl is independently optionally substituted with one, two, or threeR^(30a). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optimally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30a) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof each R^(30a) is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); and each R^(30a)is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);and each R^(30a) is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); and each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); and each R^(30a)is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R² is hydrogen orC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²is hydrogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R¹ is cycloalkyl optionally substituted with one, two, or threeR^(30a); each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl; and R² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a),each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R² is hydrogen. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is cycloalkyl optionally substituted withone, two, or three R^(30a); each R^(30a) is independently halogen; andR² is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² isC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R² is C₁-C₆ alkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is cycloalkyl optionally substituted withone, two, or three R^(30a); each R^(30a) is independently halogen; andR² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and aryl areindependently optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R isC₁-C₆ alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl; and R² is hydrogen. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30a); each R^(30a) is independently halogen; and R² is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² isC₁-C₆alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl; and R¹ is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30a); each R^(30a) is independently halogen; and R² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30b).In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30b);each R^(30b) is independently aryl optionally substituted with one, two,or three R³¹; and each R³¹ is independently halogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b); and R^(30b) is aryl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a heterocycloalkyl optionallysubstituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apiperidine or a pyrrolidine optionally substituted with one, two, orthree R^(30b). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine or a pyrrolidine optionally substitutedwith one, two, or three R^(30b); each R^(30b) is independently aryloptionally substituted with one, two, or three R³¹; and each R³¹ isindependently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apiperidine or a pyrrolidine optionally substituted with one, two, orthree R^(30b); and R^(30b) is aryl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a piperidine or a pyrrolidineoptionally substituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apiperidine optionally substituted with one, two, or three R^(30b). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apiperidine optionally substituted with one, two, or three R^(30b); eachR^(30b) is independently aryl optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine optionally substituted with one, two, orthree R^(30b); and R^(30b) is aryl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a piperidine optionallysubstituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apyrrolidine optionally substituted with one, two, or three R^(30b). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apyrrolidine optionally substituted with one, two, or three R^(30b); eachR^(30b) is independently aryl optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a pyrrolidine optionally substituted with one, two, orthree R^(30b); and R^(30b) is aryl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a pyrrolidine optionallysubstituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Z is —OR⁶⁰.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is hydrogen,—C(═O)R^(15e), —C(═O)OR^(16e), —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶⁰ is —C(═O)R^(15e), —C(═O)OR^(16e),—C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30m). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl,cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30m). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl,cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, andaryl is independently optionally substituted with one, two, or threeR^(30m). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof: R⁶⁰is cycloalkyl or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, andaryl is independently optionally substituted with one, two, or threeR^(30m). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is cycloalkyl optionally substituted with one, two, or three R^(30m). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30m).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15e) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16e) andR^(17e) are each independently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15e) is C₁-C₆ alkyl; and R^(16e) and R^(17e) are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(15e) is C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15e) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(16e) and R^(17e) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(16e) and R^(17e)are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30m) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30m) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(30m) is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Z is —SR⁶¹.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is hydrogen,—C(═O)R^(15f), —C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶¹ is —C(═O)R^(15f), —C(═O)OR^(16f),—C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30n). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl, cycloalkyl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30a). In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independentlyoptionally substituted with one, two, or three R^(30n). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is cycloalkyl orC₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl isindependently optionally substituted with one, two, or three R^(30n). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is cycloalkyloptionally substituted with one, two, or three R^(30n). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30n).

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15f) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16f) andR^(17f) are each independently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15f) is C₁-C₆ alkyl; and R^(16f) and R^(17f) are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(15f) is C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15f) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(16f) and R^(17f) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(16f) and R^(17f)are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30n) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30n) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof each R^(30n) is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Z is —CR⁶²R⁶³R⁶⁴.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶² is hydrogen,halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g),—C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionally substituted with one,two, or three R^(30o). In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁶² is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(═O)OR^(16g), —C(O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o), R^(15g) is C₁-C₆ alkyl; andR^(16g) and R^(17g) are each independently hydrogen or C₁-C₆ alkyl. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶² is hydrogen,halogen, or —OH. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶²is hydrogen or halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶² is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴³ is hydrogen,halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g),—C(O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionally substituted with one,two, or three R^(30o). In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁶³ is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o); R^(15g) is C₁-C₆ alkyl; andR^(16g) and R^(17g) are each independently hydrogen or C₁-C₆ alkyl. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶³ is hydrogen,halogen, or —OH. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶³is hydrogen or halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶³ is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁴ is —OR^(15g),—SR^(15g), —S(═O)R^(15g), —NR^(16g)R^(17g), —S(═O)₂R^(15g),—NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —C(═O)R^(16g),—C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g), —SR^(15g), —S(O)R^(15g), —NR^(16g)R^(17g), —S(═O)₂R^(15g),—NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —C(═O)OR^(16g),—C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g), —NR^(16g)R^(17g), —C(═O)R^(15g), —C(═O)OR^(16g),—C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g), —NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g) or —NR^(16g)R^(17g). In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is cycloalkyl or heterocycloalkyl; wherein each cycloalkyl andheterocycloalkyl is independently optionally substituted with one, two,or three R^(30o). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is aryl, or heteroaryl; wherein each aryl, and heteroaryl isindependently optionally substituted with one, two, or three Mo.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15g) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16g) andR^(17g) are each independently hydrogen. C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15g) is C₁-C₆ alkyl; and R^(16g) and R^(17g) are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(15g) is C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15g) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(16g) and R^(17g) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(16g) and R^(17g)are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30o) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optimally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30p) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30o) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(30o) is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), —NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30c). In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c), and each R^(30c) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen. In some embodiments of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and R^(18b) is cycloalkylor C₁-C₆ alkyl(cycloalkyl). In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); R^(18b) is cycloalkyl orC₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independently halogen orC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), Cif;alkyl(cycloalkyl), or Cif; alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptimally substituted with one, two, or three R³¹; R^(18b) is cycloalkylor C₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independently halogen.In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R^(30c); R^(18b) is cycloalkyl orC₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl, andcycloalkyl is independently optionally substituted with one, two, orthree R^(30c). In some embodiments of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl);wherein each alkyl, and cycloalkyl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof: R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with ono two, or three R^(30c); andeach R^(30c) is independently halogen. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optimally substituted with one, two, or three R^(30c); andeach R^(30c) is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl,and cycloalkyl is independently optionally substituted with one, two, orthree R^(30c); and R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl). Insome embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl,and cycloalkyl is independently optionally substituted with one, two, orthree R^(30c); R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); andeach R^(30c) is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl,and cycloalkyl is independently optionally substituted with one, two, orthree R^(30c); R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); andeach R^(30c) is independently halogen. In some embodiments of a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c);R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); and each R^(30c) isindependently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is —NH₂. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are eachindependently hydrogen, aryl, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are eachhydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are each—(CR²³R²⁴)^(w)OC(═O)OR²⁵. In some embodiments of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R²¹ and R²² are each —(CR²³R²⁴)_(w)OC(═O)OR¹⁵; w is 1 or 2;each R²³ and R²⁴ are independently hydrogen, halogen, or C₁-C₆ alkyl;and each R²⁵ is independently hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof: R²¹ and R²² are each—(CR²³R²⁴)_(w)OC(═O)OR²⁵: w is 1; R²³ and R²⁴ are hydrogen; and each R²⁵is independently hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R²¹ and R²² are each —(CR²³R²⁴)_(w)OC(═O)OR²⁵;w is 1; R²³ and R²⁴ are hydrogen; and each R²⁵ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are takentogether with the atoms to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30l).In some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are takentogether with the atoms to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30l);and each R^(30l) is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are takentogether with the atoms to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30l);and each R^(30l) is independently halogen.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments provided herein is a compound having the structureof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof:

wherein;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)RR, —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl),        alkyl(heterocycloalkyl), —S(O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a),        or —C(═O)₂R^(15a); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30a);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30o);    -   R³ is halogen, —CN, —OH, OR^(15b), SR^(18b), —NR^(16b)R^(17b),        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl),        or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), alkyl, or        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, alkyl, or        haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)^(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)—, —NR⁵⁰—, or —O—;    -   Y⁴ is —O—, —NH—, or —N(CH₃)—;    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, R⁴⁶, R⁴⁸, and R⁴⁹ are each        independently hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d),        alkyl, or haloalkyl;    -   R⁴⁴, R⁴⁷, and R⁵⁰ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30f);    -   v1, v2, and v3 are each independently 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optimally substituted with one, two,        or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g)        and R^(17a), R^(17b), R^(17b), R^(17e), R^(17f), and R^(17g) are        each independently hydrogen, alkyl, alkenyl, alkynyl,        cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, alkyl, or haloalkyl;    -   R^(18b) is alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30i);    -   R²¹ and R²² are each independently hydrogen, alkyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl),        —(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(O)R²⁶,        —(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), alkyl, or haloalkyl;    -   each R²⁵ is independently hydrogen, alkyl, alkenyl, alkynyl, or        heteroalkyl;    -   each R²⁶ is independently alkyl, alkenyl, alkynyl, or        heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), R^(30l),        R^(30n), R^(30m), and R^(30o) are independently halogen, —CN,        —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(O)NR^(c)R^(d), NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkyl(aryl),        alkyl(heteroaryl), alkyl(cycloalkyl), or        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), alkyl, haloalkyl, hydroxyalkyl, heteroalkyl,        or cycloalkyl optionally substituted with one, two, or three        halogen, alkyl, or haloalkyl;    -   each R^(a) is independently alkyl, alkenyl, alkynyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three halogen, —OH,        alkyl, or haloalkyl;    -   each R^(b) is independently hydrogen, alkyl, alkenyl, alkynyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three halogen, —OH,        alkyl, or haloalkyl;    -   R^(c) and R^(d) are each independently hydrogen, alkyl, alkenyl,        alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        halogen, —OH, alkyl, or haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, alkyl, or        haloalkyl;    -   n is 0 or 1; and    -   m is 0 or 1.

In some embodiments provided herein is a compound having the structureof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof wherein;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(O)₂R^(15a),        —S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(acyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f); C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, OR^(15b), SR^(15b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₁-C₆ cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)—, —NR⁵⁰—, or —O—;    -   Y⁴ is —O—, —NH—, or —N(CH₃)—;    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, R⁴⁶, R⁴⁸, and R⁴⁹ are each        independently hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d),        C₁-C₄ alkyl, or C₁-C₆ haloalkyl;    -   R⁴⁴, R⁴⁷, and R⁵⁰ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)OR^(b), C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30f);    -   v1, v2, and v3 are each independently 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g).    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g),        R^(17a), R^(17b), R^(17c), R^(17d), and R^(17g) are each        independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30b);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)R²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), R^(30l),        R^(30m), R^(30n), and R^(30o) are independently halogen, —CN,        —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(O)OR^(b), —C(O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(O)R^(a),        —NR^(b)C(O)OR^(b), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optimally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 0 or 1; and    -   m is 0 or 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, at least one of n orm is 1. In some embodiments of a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, nis 1. In some embodiments of a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is1 and m is 0. In some embodiments of a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, mis 1. In some embodiments of a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof m is1 and n is 0.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30a);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)²—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)— or —NR⁵⁰—, or —O—;    -   Y⁴ is —O— or —NH—;    -   R⁴⁴, R⁴⁷, and R⁵⁰ are each independently hydrogen, —S(═O)RR,        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, R⁴⁶, R⁴⁸, and R⁴⁹ are each        independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   v1, v2, and v3 are each independently 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R³⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(31b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30k), and R^(30l) is independently        halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹,    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 0 or 1; and    -   m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)— or —NR⁵⁰—;    -   Y⁴ is —O—;    -   R⁴⁴, R⁴⁷, and R⁵⁰ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, R⁴⁶, R⁴⁸ and R⁴⁹ are each independently        hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v1, v2, and v3 are each independently 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30f), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl;    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl    -   n is 0 or 1; and    -   m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁₋₆ alkyl(cycloalkyl), or C₁₋₆ alkyl(heterocycloalkyl); wherein        each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);

R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl, orcycloalkyl; wherein each alkyl, and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e);

-   -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)— or —NR⁵⁰—, or —O—;    -   Y⁴ is —O— or —NH—;    -   R⁴⁷ and R⁵⁰ are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁵, R⁴⁶, R⁴⁸ and R⁴⁹ are each independently hydrogen, halogen,        C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v2 and v3 are each independently 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30k), and R^(30l) is independently        halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 1; and    -   m is 0.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;

R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, cycloalkyl, orC₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl isindependently optionally substituted with one, two, or three R^(30a);

-   -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, —O—;    -   Y³ is —(CR⁴⁸R⁴⁹)_(v3)— or —NR⁵⁰—;    -   Y⁴ is —O—;    -   R⁴⁷ and R⁵⁰ are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁵, R⁴⁶, R⁴⁸ and R⁴⁹ are each independently hydrogen, halogen,        C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v2 and v3 are each independently 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30f), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl;    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl    -   n is 1; and    -   m is 0.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y⁴ is —O— or —NH—;    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(O)R^(a),        —S(═O)R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v1 and v2 are each independently 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);

R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,—(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or—(CR²³R²⁴)_(w)OC(═O)OR²³; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³:

-   -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30k), and R^(30l) is independently        halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₄ heteroalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 0; and    -   m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ and Q² are independently N or CW;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(31b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y⁴ is —O—;    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v1 and v2 are each independently 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)CO(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30f), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₆ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl;    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl    -   n is 0; and    -   m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ is N or CW;    -   Q² is N;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optimally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   X¹ is bond;    -   Y¹ is —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—;    -   Y⁴ is —O— or —NH—; R⁴⁵ and R⁴⁶ are each independently hydrogen,        halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v2 is 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30b);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30g),        R^(30h), R^(30i), R^(30k), and R^(30l) is independently halogen,        —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,        aryl, or heteroaryl; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 0 or 1; and    -   m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ is N or CW;    -   Q² is N;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X¹ is bond;    -   Y¹ is —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—,    -   Y⁴ is —O—;    -   R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆haloalkyl;    -   v2 is 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl,        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30k), and R^(30l) is independently        halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b), or C₁-C₆alkyl        optionally substituted with one, two, or three R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl;    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl    -   n is 0 or 1; and    -   m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ is N or CW;    -   Q² is N;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —NR^(c)R^(d), —C(═O)R^(a), —CH(═O)OR^(b), —C(═O)NR^(c)R^(d),        C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl),        C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R³⁰;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl,        heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),        C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl);        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl,        or cycloalkyl; wherein each alkyl, and cycloalkyl is        independently optionally substituted with one, two, or three        R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y⁴ is —O— or —NH—;    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v1 and v2 are each independently 1-3;    -   R^(15c) is C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16c) is hydrogen or C₁-C₆ alkyl optionally substituted with        one, two, or three R^(30h);    -   R^(18b) is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(cycloalkyl), or        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,        and heterocycloalkyl is independently optionally substituted        with one, two, or three R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(36b), R^(31c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30k), and R^(30l) is independently        halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or C₁-C₆ heteroalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   n is 0; and    -   m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ is N or CW;    -   Q² is N;    -   each W is hydrogen;    -   Z is —NR¹R²;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,        cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,        cycloalkyl, and aryl is independently optionally substituted        with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R³ is halogen;    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH, or        —OR^(15c);    -   R⁵ and R⁶ are each hydrogen;    -   R⁸ is hydrogen;    -   R⁹ and R¹⁰ are each hydrogen;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   Y⁴ is —O—;    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein each        alkyl, cycloalkyl, and heterocycloalkyl is independently        optionally substituted with one, two, or three R^(30f);    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v1 and v2 are each independently 1 or 2;    -   R^(15c) is C₁-C₆ alkyl;    -   R²¹ and R²² are each hydrogen, C₁-C₂₀ alkyl.        —(CR²³R²⁴)_(w)OC(═O)OR²⁵, or aryl optionally substituted with        one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen;    -   each R²⁵ is independently hydrogen or C₁-C₆ alkyl;    -   each w is independently 1 or 2;    -   each R^(30a), R^(30b), R^(30f), R^(30k), and R^(30l) is        independently halogen, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),        or C₁-C₄ alkyl optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —OH, —OR^(a), or        —NR^(c)R^(d);    -   each R^(a) is independently C₁-C₆ alkyl;    -   each R^(b) is independently hydrogen or C₁-C₆ alkyl;    -   R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen or C₁-C₆ alkyl    -   n is 0; and    -   m is 1.

For any and all of the embodiments of Formula (II), substituents areselected from among a subset of the listed alternatives.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁸ is hydrogen,halogen, —OH, —OMe, —NH₁, —NH(CH₃), —N(CH₃)₂, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁸is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁸ is hydrogen,halogen, —OH, —NH₂, or C₁-C₆ alkyl. In some embodiments of a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof; R⁸ is hydrogen or C₁-C₆ alkyl. In some embodimentsof a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁸ is hydrogen.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁹ and R¹⁰ are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁹ and R¹⁰ are each hydrogen.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, m is 1. In someembodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, m is 1; and n is 0.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y⁴ is —O—. In someembodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y⁴ is —NH—. In someembodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Y⁴ is —N(CH₃)—.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, the compound ofFormula (II) is of Formula (IIa):

In some embodiments of a compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof;

-   -   A is —O— or —CH₂—;    -   Q¹ is CW and Q² is N; or    -   Q¹ is N and Q² is N;    -   W is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),        —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a),        —S(═O)₂NR^(C)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₄-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)R^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(15g)C(═O)NR^(16g)R^(17g),        —NR^(16h)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16c)S(═O)₂R^(15d), —NR^(16d)C(O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   X¹ is a bond;    -   Y¹ is —S(═O)₂—;    -   Y² is —(CR⁴⁵R⁴⁶⁾ _(v2)—;    -   R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   v2 is 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(17a),        R^(17b), R^(17e), R^(17f), and R^(17g) are each independently        hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)CO(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optimally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30g)        and R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m),        R^(30n), and R^(30o) are independently halogen, —CN, —OH,        —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)—NR^(c)NR^(d), —NR^(b)C(═O)NR^(c)R^(d),        —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R,        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(CO)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —(CR⁴²R⁴³)_(v1)—. In some embodiments of a compound of Formula (II)or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Y¹ is —(CR⁴²R⁴³)_(v1)—; and v1 is 1 or 2. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —(CR⁴²R⁴³)_(v1)—; and v1 is 1. In some embodiments of a compound ofFormula (II) or (IIa), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, Y¹ is —(CR⁴²R⁴³)_(v1)—; and v1 is 2. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof; Y¹is —(CR⁴²R⁴³)_(v1)—; and R⁴² and R⁴³ are each independently hydrogen,halogen, or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II) or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Y¹ is —(CR⁴²R⁴³)_(v1)—; and R⁴² and R⁴³ are eachhydrogen. In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —(CR⁴²R⁴³)_(v1)—; R⁴² and R⁴³ are each independently hydrogen,halogen, or C₁-C₆ alkyl; and v1 is 1 or 2. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, Y¹ is —(CR⁴²R⁴³)_(v1)—; R⁴² andR⁴³ are each hydrogen; and v1 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —NR⁴⁴—. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,Y¹ is —NR⁴⁴—; and R⁴⁴ is hydrogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, Y¹ is —NR⁴⁴—; and R⁴⁴ ishydrogen. In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Y¹is —NR⁴⁴—; and R⁴⁴ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —O—.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —S(═O)₂—.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond. In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —C(═O)—. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X¹ is —S(═O)₂—.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —CR⁴⁰R⁴¹—. In some embodiments of a compound of Formula (II) or(IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, X¹ is —CR⁴⁰R⁴¹—; and R⁴⁰ and R⁴¹ are each independentlyhydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X¹ is —CR⁴⁰R⁴¹—; and R⁴⁰ and R⁴¹ are each independently hydrogen,halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is —CR⁴⁰R⁴¹—; and R⁴⁰ and R³¹are each independently C₁-C₆ alkyl or —OH.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond, —C(═O)—, —S(═O)₂—, or —CR⁴⁰R⁴¹—; Y¹ is —(CR⁴²R⁴³)_(v1)—,—NR⁴⁴—, or —O—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond or —CR⁴⁰R⁴¹—; Y¹ is —(CR⁴²R⁴³)_(v1)—, —S(═O)²—, —NR⁴⁴—, or —O—;and Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —C(═O)—; Y¹ is —(CR⁴²R⁴³)O—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —C(═O)—; Y¹ is —(CR⁴²R⁴³)_(v1)—: Y² is —(CR⁴³R⁴⁶)O—; R⁴² and R⁴³ areeach independently hydrogen, halogen, or C₁-C₆ alkyl; v1 is 1 or 2; R⁴⁵and R⁴⁶ are each independently hydrogen, halogen, or C₁-C₆ alkyl; and v2is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X¹ is —C(═O)—; Y¹ is —(CR⁴²R⁴³)_(v1)—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴² andR⁴³ are each hydrogen; v1 is 1; R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —CR⁴⁰R⁴¹—; Y¹ is —(CR⁴²R⁴³)_(v1)—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. Insome embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —CR⁴⁰R⁴¹—; Y¹ is —(CR⁴²R⁴³)_(v1)—; Y² is —(CR⁴³R⁴⁶)_(v2)—; R⁴⁰ andR⁴¹ are each independently hydrogen, halogen, —OH, or C₁-C₆ alkyl; R⁴²and R⁴³ are each independently hydrogen, halogen, or C₁-C₆ alkyl: v1 is1 or 2; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, or C₁-C₆alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula(II) or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X¹ is —CR⁴⁰R⁴¹—; Y¹ is —(CR⁴²R⁴³)_(v1)—; Y² is—(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁰ and R⁴¹ are each independently hydrogen, —OH, orC₁-C₆ alkyl; R⁴² and R⁴³ are each hydrogen; v1 is 1; R⁴⁵ and R⁴⁶ areeach hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —C(═O)—; Y¹ is —O—; and Y² is —NR⁴⁷—. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is —C(═O)—; Y¹ is —O—; Y² is—NR⁴⁷—; and R⁴⁷ is hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is —C(═O)—; Y¹ is —O—; Y² is—NR⁴⁷—; and R⁴⁷ is hydrogen. In some embodiments of a compound ofFormula (II) or (IIa), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X¹ is —C(═O)—: Y¹ is —O—; Y² is —NR⁴⁷—; and R⁴⁷is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —(CR⁴²R⁴³)_(v1)—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—: Y¹ is —(CR⁴⁵R⁴⁶)_(v1)—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴² and R⁴³are each independently hydrogen, halogen, or C₁-C₆ alkyl; v1 is 1 or 2;R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, or C₁-C₆ alkyl;and v2 is 1 or 2. —. In some embodiments of a compound of Formula (II)or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X¹ is —S(═O)₂—; Y¹ is —(CR⁴²R⁴³)_(v1)—; Y² is—(CR⁴⁵R⁴⁶)_(v2)—; R⁴² and R⁴³ are each hydrogen; v1 is 1; R⁴⁵ and R⁴⁶are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —NR⁴⁴—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)_(v)—; Y¹ is —NR⁴⁴—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁴ is hydrogen orC₁-C₆ alkyl; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, orC₁-C₆ alkyl; and v2 is 1 or 2. In some embodiments of a compound ofFormula (II) or (IIa), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X¹ is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is—(CR⁴⁵R⁴⁶)^(v2)—; R⁴⁴ is hydrogen; R⁴⁵ and R⁴⁶ are each hydrogen; and v2is 1. In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁴ is C₁-C₆ alkyl;R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —(CR⁴²R⁴³)_(v1)—; and Y² is —NR⁴⁷—. In someembodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —(CR⁴²R⁴³)_(v1)—: Y² is —NR⁴⁷—; R⁴² and R⁴³ are eachindependently hydrogen, halogen, or C₁-C₆ alkyl: v1 is 1 or 2; and R⁴⁷is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II) or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X¹ is —S(═O)₂—; Y¹ is —(CR⁰²R⁴³)_(v1)—; Y² is—NR⁴⁷—; R⁴² and R⁰³ are each hydrogen; v1 is 1; and R⁴⁷ is hydrogen. Insome embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —(CR⁴²R⁴³)_(v1)—; Y² is —NR⁴⁷—; R⁴² and R⁴³ are eachhydrogen; v1 is 1; and R⁴⁷ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —NR⁴⁴—; and Y² is —NR⁴⁷—. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y²is —NR⁴⁷—; R⁴⁴ is hydrogen or C₁-C₆ alkyl; and R⁴⁷ is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is —NR⁴⁷—; R⁴⁴ is hydrogen; and R⁴⁷ ishydrogen. In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is —NR⁴⁷—; R⁴⁴ is C₁-C₆ alkyl; and R⁴⁷ isC₁-C₆ alkyl. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X¹ is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is —NR⁴⁷—; R⁴⁴ is hydrogen; and R⁴⁷ isC₁-C₆ alkyl. In some embodiments of a compound of Formula (II) or (IIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,X¹ is —S(═O)₂—; Y¹ is —NR⁴⁴—; Y² is —NR⁴⁷—; R⁴⁴ is C₁-C₆ alkyl; and R⁴⁷is hydrogen.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond; Y¹ is —O—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is bond; Y¹ is —O—; Y² is—(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen,or C₁-C₆ alkyl; and v2 is 1 or 2. In some embodiments of a compound ofFormula (II) or (IIa), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X¹ is bond; Y¹ is —O—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—;R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond; Y¹ is —S(═O)₂—; and Y² is —(CR⁴⁵R⁴⁶)_(v2)—. In some embodimentsof a compound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is bond: Y¹ is —S(═O)₂—; Y²is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁵ and R⁴⁶ are each independently hydrogen,halogen, or C₁-C₆ alkyl; and v2 is 1 or 2. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is bond; Y¹ is —S(═O)₂—; Y²is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond; Y¹ is —NR⁴⁴—; and Y¹ is —(CR⁴⁵R⁴⁶)_(v2)—. In some embodimentsof a compound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is bond; Y is —NR⁴⁴—; Y² is—(CR⁴⁵SR⁴⁶)_(v2)—; R⁴⁴ is hydrogen, C₁-C₆ alkyl, —S(═O)₂R^(a), or—C(═O)R^(a); R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, orC₁-C₆ alkyl; and v2 is 1 or 2. In some embodiments of a compound ofFormula (II) or (IIa), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, X¹ is bond; Y¹ is —NR⁴⁴—; Y² is—(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁴ is hydrogen or C₁-C₆ alkyl, R⁴⁵ and R⁴⁶ are eachhydrogen; and v2 is 1. In some embodiments of a compound of Formula (II)or (IIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, X¹ is bond: Y¹ is —NR⁴⁴—; Y² is —(CR⁴⁵R⁴⁶)_(r):R⁴⁴ is —S(═O)₂R^(a) or —C(═O)R^(a), R⁴⁵ and R⁴⁶ are each hydrogen; andv2 is 1. In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X¹is bond; Y¹ is —NR⁴⁴—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁴ is —C(═O)R^(a), R⁴⁵and R⁴⁶ are each hydrogen; and v2 is 1. In some embodiments of acompound of Formula (II) or (IIa), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, X¹ is bond; Y¹ is —NR⁴⁴—; Y¹ is—(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁴ is —C(═O)R^(a), R⁴⁵ and R⁴⁶ are each hydrogen; andv2 is 1.

In some embodiments of a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, the compound ofFormula (II) is of Formula (IIb):

In some embodiments of a compound of Formula (II) or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y³is —(CR⁴⁸R⁴⁹)_(v3)—. In some embodiments of a compound of Formula (II)or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Y³ is —(CR⁴⁸R⁴⁹)_(v3)—; R⁴⁸ and R⁴⁹ are eachindependently hydrogen, halogen, or C₁-C₆ alkyl; and v3 is 1 or 2. Insome embodiments of a compound of Formula (II) or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y³is —(CR⁴⁸R⁴⁶)_(v3)—; R⁴⁸ and R⁴⁹ are each hydrogen; and v3 is 1.

In some embodiments of a compound of Formula (II) or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y³is —NR⁵⁰—. In some embodiments of a compound of Formula (II) or (IIb),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,Y³ is —NR⁵⁰—; and R⁵⁰ is hydrogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (II) or (IIb), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, Y³ is —NR⁵⁰—; and R⁵⁰ ishydrogen. In some embodiments of a compound of Formula (II) or (IIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y³is —NR⁵⁰—; and R⁵⁰ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II) or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y³is —O—.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —(CR⁴⁵R⁴⁶)_(v2)—. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁵ and R⁴⁶ are eachindependently hydrogen, halogen, or C₁-C₆ alkyl; and v2 is 1 or 2. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y²is —(CR⁴⁵R)_(v2)—; R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y¹is —NR⁴⁷—. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, Y² is —NR⁴⁷—; and R⁴⁷ is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y²is —NR⁴⁷—; and R⁴⁷ is hydrogen. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, Y² is —NR⁴⁷—; and R⁴⁷ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y²is —O—.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y²is —O— and Y³ is —(CR⁴⁸R⁴⁹)_(v3)—. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, Y² is —O—; Y³ is —(CR⁴⁸R⁴⁹)₃—; R⁴⁸ andR⁴⁹ are each independently hydrogen, halogen, or C₁-C₆ alkyl; and v3 is1 or 2. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, Y² is —O—; Y³ is —(CR⁴⁸R⁴⁹)_(v3)—; R⁴⁸ and R³⁹ are eachhydrogen; and v3 is 1.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is N; and Q² is CW. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, Q¹ is CW; and Q² is N. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Q¹ is N; and Q² is N.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is CW; and Q² is CW.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachW is independently hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachW is independently hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰; andeach R³⁰ is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each W is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is—O—. In some embodiments of a compound of Formula (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,A is —CH₂—.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵and R⁶ are each independently hydrogen, halogen, C₁₋₆ alkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e). In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e); and each R^(30e)is independently halogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁵ and R⁶ are eachhydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen, —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30d). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are eachindependently hydrogen, halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c),—NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30d); and each R^(30d) is independently halogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen. —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), or —NR^(16c)C(═O)R^(15c). In some embodiments ofa compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are eachindependently hydrogen, halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c),or —NR^(16c)C(═O)R^(15c); R^(15c) are each independently C₁-C₆ alkyl orC₁-C₆ haloalkyl; and R^(16c) are each independently hydrogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁴ and R⁷ are each independently hydrogen,halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c), or—NR^(16c)C(═O)R^(15c); R^(15c) are each independently C₁-C₆ alkyl; andR¹⁶ are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen, or —OH. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently halogen or —OH. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁴ and R⁷ are each—OH.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—NR¹R².

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, oneof R¹ or R² is not hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30a). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(O)₂R^(15a),—S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(13a); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a); R^(15a) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16a) andR^(17a) are each independently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)—R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optimally substituted with one, two, orthree R^(34′); Ma is C₁-C₆ alkyl; and R^(16a) and R^(17a) are eachindependently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl),C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30A). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(═O)₂R^(15A),—S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a); R_(15a) is C₁-C₆alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and R^(16a) andR^(17a) are each independently hydrogen. C₁-C₆ alkyl, aryl, or C₁-C₆alkyl(aryl); wherein each alkyl and aryl is optionally substituted withone, two, or three halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(═O)₂R^(15a),—S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a); R^(15a) is C₁-C₆alkyl; and R^(16a) and R^(17a) are each independently hydrogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen; andR^(16a) and R^(17a) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹⁵ is C₁-C₆ alkyl;and R^(16a) and R^(17a) are each independently hydrogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) is C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R^(16a) and R^(17a) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16a) and R^(17a) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R³¹%. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R^(30a). In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate;or stereoisomer thereof, R¹ is cycloalkyl or C₁-C₆ alkyl(aryl); whereineach alkyl, cycloalkyl, and aryl is independently optionally substitutedwith one, two, or three R^(30a). In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R¹ is cycloalkyl optionallysubstituted with one, two, or three R^(30a). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a).

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH. —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30a) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), —C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (II), (ha), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, each R^(30a) is independently halogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30a) is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R is cycloalkyl optionally substituted withone, two, or three R^(30a); and each R^(30a) is independently halogen,—CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodimentsof a compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); and each R^(30a)is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkaryl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); and each R^(20a)is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof: R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and aryl areindependently optionally substituted with one, two, or three R^(30a);and each R^(30a) is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R² is hydrogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; each R³¹ is independentlyhalogen or C₁-C₆ alkyl; and R² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen; and R² is hydrogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; each R³¹ is independentlyhalogen or C₁-C₆ alkyl; and R² is hydrogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl; and R¹ is hydrogen. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R¹ is cycloalkyl optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a);each R^(10a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; each R³¹ is independentlyhalogen or C₁-C₆ alkyl; and R² is C₁-C₆ alkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is cycloalkyloptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl; and R² is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R¹ is cycloalkyl optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30a); each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl; and R² is hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² ishydrogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and aryl areindependently optionally substituted with one, two, or three R^(30a);each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R² is hydrogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a); each R^(30a) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; each R³¹ is independently halogen or C₁-C₆ alkyl; and R² isC₁-C₆ alkyl. In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30a); each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl; and R² is C₁-C₆ alkyl. In some embodiments ofa compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30a); each R^(30a) isindependently halogen; and R² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b). In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a heterocycloalkyl optionallysubstituted with one, two, or three R^(30b); each R^(30b) isindependently aryl optionally substituted with one, two, or three R³¹;and each R³¹ is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b); and R^(30b) is aryl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form aheterocycloalkyl optionally substituted with one R^(30b); and R³⁰ isaryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine or a pyrrolidine optionally substitutedwith one, two, or three R^(30b). In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R¹ and R² are taken together with thenitrogen atom to which they are attached to form a piperidine or apyrrolidine optionally substituted with one, two, or three R^(30b); eachR^(30b) is independently aryl optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form a piperidine or a pyrrolidine optionallysubstituted with one, two, or three R^(30b); and R^(30b) is aryl. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine or a pyrrolidine optionally substitutedwith one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine optionally substituted with one, two, orthree R^(30b). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate or stereoisomerthereof, R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form a piperidine optionally substituted with one,two, or three R^(30b); each R^(30b) is independently aryl optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apiperidine optionally substituted with one, two, or three R^(30b); andR^(30b) is aryl. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a piperidine optionallysubstituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a pyrrolidine optionally substituted with one, two, orthree R^(30b). In some embodiments of a compound of Formula (II). (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate or stereoisomerthereof, R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form a pyrrolidine optionally substituted with one,two, or three R^(30b); each R^(30b) is independently aryl optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ and R² are takentogether with the nitrogen atom to which they are attached to form apyrrolidine optionally substituted with one, two, or three R^(30b); andR^(30b) is aryl. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ and R² are taken together with the nitrogenatom to which they are attached to form a pyrrolidine optionallysubstituted with one R^(30b); and R^(30b) is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—OR⁶⁰.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is hydrogen. —C(═O)R^(15e), —C(═O)OR^(16e), —C(═O)NR^(16e)R^(17e). C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is —C(═O)R^(15e),—C(═O)OR^(16e), —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m).

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30m). Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R^(30m). In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶⁰ is cycloalkyl or C₁-C₆ alkyl(aryl); whereineach alkyl, cycloalkyl, and aryl is independently optionally substitutedwith one, two, or three R^(30m). In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁶⁰ is cycloalkyl optionallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30m).

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15e) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen; andR^(16e) and R^(17e) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15e) is C₁-C₆alkyl; and R^(16e) and R^(17e) are each independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15e) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15e) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R^(16e) and R^(17c) are eachindependently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(16e) and R^(17e) are each independently hydrogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30m) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30m) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30m) is independently halogen, —CN, —OH,—OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30m) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(30m) is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—SR⁶¹.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶¹is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is —C(═O)R^(15f),—C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30a). In some embodiments of acompound of Formula (II). (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl,cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30n). In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶¹is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R^(30n). In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶¹ is cycloalkyl or C₁-C₆ alkyl(aryl); whereineach alkyl, cycloalkyl, and aryl is independently optimally substitutedwith one, two, or three R^(30n). In some embodiments of a compound ofFormula (II), (IIa), or (Lib), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁶¹ is cycloalkyl optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆alkyl(aryl); wherein alkyl and aryl are independently optionallysubstituted with one, two, or three R^(30n).

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15f) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen; andR^(16f) and R^(17f) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Rim is C₁-C₆ alkyl;and R^(16f), and R^(17f) are each independently hydrogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15f) is C₁-C₆ alkyl, aryl, or C₁-C₄ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15f) is C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R^(16f) and R^(17f) are each independentlyhydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16f) and R^(17f) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (Lib), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH. —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30n) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)R^(b), —C(O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30n) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is independently optionally substituted with one,two, or three R³¹; and each R³¹ is independently C₁-C₆ alkyl. In someembodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30n) is independently halogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30n) is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—CR⁶²R⁶³R⁶⁴.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶²is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶¹ is hydrogen,halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g),—C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionally substituted with one,two, or three R^(30o); R^(15g) is C₁-C₆ alkyl; and R^(15g) and R^(17g)are each independently hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, sol vale, or stereoisomer thereof, R⁶² is hydrogen,halogen, or —OH. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶² is hydrogen or halogen. In some embodiments ofa compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶² is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶³is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(O)OR^(16g), —C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶³ is hydrogen,halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g),—C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionally substituted with one,two, or three R^(30o); R^(15g) is C₁-C₆ alkyl; and R^(16g) and R^(17g)are each independently hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶³ is hydrogen,halogen, or —OH. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof: R⁶³ is hydrogen or halogen. In some embodiments ofa compound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶³ is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g), —SR^(15g), —S(═O)R^(15g), —NR^(16g)R^(17g),—S(═O)₂R^(15g), —NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is —OR^(15g), —SR^(15g), —S(═O)R^(15g),—NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),—S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —C(O)OR^(16g),—C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optimally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is —OR^(15g), —NR^(16g)R^(17g), —C(═O)R^(15g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is —OR^(15g), —NR^(16g)R^(17g), cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(31o). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁴ is —OR^(15g) or—NR^(16g)R^(17g). In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁴ is cycloalkyl or heterocycloalkyl; whereineach cycloalkyl and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R⁶⁴ is aryl, orheteroaryl; wherein each aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30o).

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15g) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen; andR^(16g) and R^(17g) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R^(15g) is C₁-C₆alkyl; and R^(16g) and R^(17g) are each independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15g) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(15g) is C₁-C₆ alkyl. In some embodiments of a compound ofFormula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R^(16g) and R^(17g) are eachindependently hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(16g) and R^(17g) are each independently hydrogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30o) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹; and each R³¹ is independently halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (II). (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)R^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30o) is independently halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹; and each R³¹ is independentlyC₁-C₆ alkyl. In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30o) is independently halogen, —CN, —OH,—OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(30o) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(30o) is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), —NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen. —CN.—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), —NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R³ is halogen, —CN,—SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkyl(aryl),C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30c); and R^(18b) iscycloalkyl or C₁-C₆ alkyl(cycloalkyl). In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); R^(18b) is cycloalkyl orC₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independently halogen orC₁-C₆ alkyl. In some embodiments of a compound of Formula (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c); R^(18b) is cycloalkyl orC₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independently halogen. Insome embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30c); R^(18b) iscycloalkyl or C₁-C₆ alkyl(cycloalkyl); and each R^(30c) is independentlyC₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl);wherein each alkyl, and cycloalkyl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R¹ is halogen, —CN.—SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl,and cycloalkyl is independently optionally substituted with one, two, orthree R^(30c); and each R^(30c) is independently halogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl);wherein each alkyl, and cycloalkyl is independently optionallysubstituted with one, two, or three R^(30c); and each R^(30c) isindependently halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c);and each R^(30c) is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or Mb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, or C₁-C₆ alkyl(cycloalkyl);wherein each alkyl, and cycloalkyl is independently optionallysubstituted with one, two, or three R^(30c); and R^(18b) is cycloalkylor C₁-C₆ alkyl(cycloalkyl). In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c);R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); and each R^(30c) isindependently halogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R³ is halogen, —CN, —SR^(18b), C₁-C₆alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c);R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); and each R^(30c) isindependently halogen. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl, orC₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c);R^(18b) is cycloalkyl or C₁-C₆ alkyl(cycloalkyl); and each R^(30c) isindependently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen. In some embodiments of a compound of Formula (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R³ is —NH₂.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are each independently hydrogen, aryl, or—(CR²³R²⁴)_(w)OC(═O)OR²⁵.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are each hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are each —(CR²³R¹⁴)_(w)OC(═O)OR²⁵. In some embodiments of acompound of Formula (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, R²¹ and R²² are each—(CR²³R²⁴)OC(═O)OR²⁵; w is 1 or 2; each R²³ and R²⁴ are independentlyhydrogen, halogen, or C₁-C₆ alkyl; and each R²³ is independentlyhydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R²¹ and R²² are each —(CR²³R²⁴)_(w)OC(═O)OR²⁵;w is 1: R²³ and R²⁴ are hydrogen; and each R²⁵ is independently hydrogenor C₁-C₆ alkyl. In some embodiments of a compound of Formula (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R²¹ and R²² are each —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wis 1; R²³ and R²⁴ are hydrogen; and each R²⁵ is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are taken together with the atoms to which they are attached toform a heterocycloalkyl optionally substituted with one, two, or threeR^(30l). In some embodiments of a compound of Formula (II) or (IIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R²¹ and R²² are taken together with the atoms to which they are attachedto form a heterocycloalkyl optionally substituted with one, two, orthree R^(30l); and each R^(30l) is independently halogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (II) or (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are taken together with the atoms to which they are attached toform a heterocycloalkyl optionally substituted with one, two, or threeR^(30l); and each R^(30l) is independently halogen.

In some embodiments provided herein is a compound having the structureof Formula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof:

wherein;

-   -   Q³ and Q⁴ are independently N or CW¹; provided that at least one        of Q³ or Q⁴ is N;    -   W¹ is hydrogen, halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   A is —O— or —CH₂—;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —S(═O)₂R^(15a), —S(C))₂NR^(16a)R^(17a), or —C(═O)₂R^(15a);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen. —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)R^(15g), —NHS(═O)₂R^(15g),        —S(O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30o);    -   R³ is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30o);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, —O—, or —CR³⁰R⁴¹—;    -   Y¹ is —C(═O)—, —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, —S—, or —O—;    -   Y² is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷—, or —O—;    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30p);    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(═O)R^(a),        —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or        heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30f);    -   v1 and v2 are each independently 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g)        and R^(17a), R^(17b), R^(17e), R^(17f), and R^(17g) are each        independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30h);    -   or R^(16a) and R^(17a) or R^(1b6) and R^(17b) or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)CO(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g), R^(30h), R^(30i), R^(30j), R^(30k), R^(30l), R^(30m),        R^(30n), R^(30o), and R^(30p) are independently halogen, —CN,        —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d),        —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is        independently optionally substituted with one, two, or three        R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(O)OR^(b), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

In some embodiments provided herein is a compound having the structureof Formula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof:

wherein;

-   -   Q¹ and Q² are independently N or CW;    -   Q³ and Q⁴ are independently N or CW¹; provided that at least one        of Q³ or Q⁴ is N;    -   each W is independently hydrogen, halogen, —CN, —OH, —OR^(a),        —SH, —SR^(a), —S(═O)R^(a), —NO₂. —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R³⁰;    -   W¹ is hydrogen, halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   A is —O— or —CH₂—;    -   Z is —NR¹R², —OR⁶⁰, —SR⁶¹, or —CR⁶²R⁶³R⁶⁴;    -   R¹ and R² are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),        —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a);        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30a);    -   or R¹ and R² are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three R^(30b);    -   R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),        —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30m);    -   R⁶¹ is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f),        —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30n);    -   R⁶², R⁶³, and R⁶⁴ are each independently hydrogen, halogen, —CN,        —OH, —OR^(15g), —SH, —SR^(15g), —S(═O)R^(15g), —NO₂,        —NR^(16g)R^(17g), —S(═O)₂R^(15g), —NHS(═O)₂R^(15g),        —S(O)₂NR^(16a)R^(17a), —C(═O)R^(15g), —OC(═O)R^(15g),        —C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),        —OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),        —N^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,        C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R^(30c);    -   R³ is halogen, —CN, —OH, —OR¹⁵b, —SR^(18b), —NR^(16b)R^(17b),        C₁-C₆ alkyl, C₁-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆        alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆        alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30c);    -   R⁴ and R⁷ are each independently hydrogen, halogen, —OH,        —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30d);    -   R⁵ and R⁶ are each independently hydrogen, halogen, —OH,        —OR^(15d), —NR^(16d)S(═O)₂R^(15d), —NR^(16d)C(═O)R^(15d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one,        two, or three R^(30e);    -   R⁸ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   X¹ is bond, —C(═O)—, —S(═O)₂—, —O—, or —CR⁴⁰R⁴¹—;    -   Y¹ is —C(═O)—, —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, —S—, or —O—;    -   Y¹ is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷— or —O—;    -   R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, and R⁴⁶ are each independently        hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₁-C₆ alkynyl, cycloalkyl, or heterocycloalkyl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and        heterocycloalkyl is independently optionally substituted with        one, two, or three R^(30p);    -   R⁴⁴ and R⁴⁷ are each independently hydrogen, —S(═O)R^(a),        —S(═O)—R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or        heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30f);    -   v1 and v2 are each independently 1-3;    -   R^(15a), R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g)        are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30g);    -   R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g)        and R^(17a), R^(17b), R^(17e), R^(17f), and R^(17g) are each        independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is        independently optionally substituted with one, two, or three        R^(30h);    -   or R^(16a) and R^(17a) or R^(16b) and R^(17b), or R^(16e) and        R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) are taken        together with the nitrogen atom to which they are attached to        form a heterocycloalkyl optionally substituted with one, two, or        three halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   R^(18b) is C₁-C₆ alkyl, C₂-C₈ alkenyl, C₂-C₆ alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one, two, or three        R^(30i);    -   R²¹ and R²² are each independently hydrogen, C₁-C₂₀alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆        alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),        C₁-C₆ alkyl(heterocycloalkyl), —(CR²³R²⁴)_(w)C(═O)OR²⁵,        —(CR²³R²⁴)_(w)OC(═O)R²⁶, —(CR²³R²⁴)_(w)SC(═O)R²⁶, or        —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one, two, or three R^(30k);    -   or R²¹ and R²² are taken together with the atoms to which they        are attached to form a heterocycloalkyl optionally substituted        with one, two, or three R^(30l);    -   each R²³ and R²⁴ are independently hydrogen, halogen, —OH,        —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R²⁵ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl;    -   each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, or C₁-C₆ heteroalkyl;    -   each w is independently 1-4;    -   each R³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30f),        R^(30g) and R^(30h), R^(30i), R^(30j), R^(30k), R^(30l),        R^(30m), R^(30n), R^(30o), and R^(30p) are independently        halogen, —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a), —NO₂,        —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₃NR^(c)R^(d),        —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b),        —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d),        —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆        alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three R³¹;    -   each R³¹ is independently halogen, —CN, —OH, —OR^(a), —SH,        —SR^(a), —S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(O)R^(a),        —NR^(b)C(O)OR^(b), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optimally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optimally substituted with one, two, or three        halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl; and    -   R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,        alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,        aryl, and heteroaryl is independently optionally substituted        with one, two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one, two, or three halogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl.

For any and all of the embodiments of Formula (III) or (IV),substituents are selected from among a subset of the listedalternatives.

In some embodiments of a compound of formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, when

then one of R⁴⁵ or R⁴⁶ is not hydrogen.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, the compound is not(1-((5-(2-chloro-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2,2,2-trifluoroethyl)phosphonicacid or any stereoisomers thereof.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, Q¹ is N; and Q² isCW. In some embodiments of a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q¹is CW; and Q² is N. In some embodiments of a compound of Formula (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,Q¹ is CW; and Q² is CW. In some embodiments of a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, Q¹ is N; and Q² is N. In some embodiments of a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰. Insome embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl,is independently optionally substituted with one, two, or three R³⁰. Insome embodiments of a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each W isindependently hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each W is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³⁰ is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R³⁰ is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³⁰ is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³⁰ is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³⁰ is independently halogen, or C₁-C₆ alkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R³⁰ is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁸is hydrogen, halogen, —OH, —OMe, —NH₂, —NH(CH₃), —N(CH₃)₂, C₁-C₆ alkyl,or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula (III)or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁸ is hydrogen, halogen, —OH, —NH₂, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁸ is hydrogen, halogen, —OH, —NH₂, or C₁-C₆ alkyl. In some embodimentsof a compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁸ is hydrogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁸is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁹and R¹⁰ are each independently hydrogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁹and R¹⁰ are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q³is N and Q⁴ is CW¹. In some embodiments of a compound of Formula (III)or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, Q⁴ is N and Q³ is CW¹. In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, Q³ is N and Q⁴ is N.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, W¹is hydrogen, halogen, or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, W¹ is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is—O—. In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is—CH₂—.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, v1is 1 or 2. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,v1 is 1. In same embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v1is 2.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2is 1 or 2. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:v2 is 1. In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2is 2.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof.

and when

then

-   -   R⁴⁵ is halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein        each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl        is independently optionally substituted with one, two, or three        R^(31p); and    -   R⁴⁶ is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or        heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, and heterocycloalkyl is independently optionally        substituted with one, two, or three R^(30p).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁰and R⁴¹ are each independently hydrogen, halogen, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein eachalkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30p). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁰ and R⁴¹ are eachindependently hydrogen, halogen. —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁴⁰ and R⁴¹ are each independently hydrogen,halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁰ and R⁴¹ are eachindependently hydrogen, halogen, or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁰ and R⁴¹ are eachindependently hydrogen or halogen. In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁴⁰ and R⁴¹ are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴²and R⁴³ are each independently hydrogen, halogen, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein eachalkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30p). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴² and R⁴³ are eachindependently hydrogen, halogen, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁴² and R⁴³ are each independently hydrogen, halogen, —OH, —OR^(a), orC₁-C₆ alkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁴² and R⁴³ are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁴is hydrogen, —S(═O)₂R^(a), —C(═O)R^(a), C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₁-C₆ alkyl(aryl). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁴⁴ is hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁴ is hydrogen. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁴is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁵and R⁴⁶ are each independently hydrogen, halogen, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein eachalkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30p). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁵ and R⁴⁶ are eachindependently hydrogen, halogen, C₁-C₆ alkyl, or cycloalkyl; whereineach alkyl and cycloalkyl is independently optionally substituted withone, two, or three R^(30p). In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁴⁵ and R⁴⁶ are each independently hydrogen,halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(aryl), or cycloalkyl. In some embodimentsof a compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁵ and R⁴⁶ are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R⁴⁵ and R⁴⁶ are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁵is halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkylis independently optionally substituted with one, two, or three R^(30p);and T⁴⁶ is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁴⁵ is halogen, C₁-C₆ alkyl, or cycloalkyl;wherein each alkyl and cycloalkyl is independently optionallysubstituted with one, two, or three R^(30p); and R⁴⁶ is hydrogen orC₁-C₆ alkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁴⁵ is halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(aryl), or cycloalkyl; and R⁴⁶ is hydrogenor C₁-C₆ alkyl. In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁴⁵ is C₁-C₆ alkyl; and R⁴⁶ is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(30p) is halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(30p) is halogen, —OH,—OR^(a), C₁-C₆ alkyl, cycloalkyl, or aryl; wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R³¹. In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(30p) is —OH, cycloalkyl, or aryl; wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R³¹. In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(30p) is —OH, cycloalkyl, or aryl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30p) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30p) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30p) is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30p) is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30p) is independently halogen, or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30p) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁷is hydrogen. —S(═O)₂R^(a), —C(═O)R^(a), C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₁-C₆ alkyl(aryl). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁴⁷ is hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴⁷ is hydrogen. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴⁷is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e). In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵and R⁶ are each independently hydrogen, halogen, C₁-C₆ alkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e). In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁵and R⁶ are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15d) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15d) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(15d) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16d) is hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16d) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16d) is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30C) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30e) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30e) is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30e) is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30e) is independently halogen, or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30e) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen, —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30d). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴ and R⁷ are each independentlyhydrogen, halogen, —OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c),—NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30d). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁴ and R⁷ are each independently hydrogen, halogen, —OH,—OR^(15c), —NR^(16c)S(═O)₂R^(15c), or —NR^(16c)C(═O)R^(15c).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently hydrogen, halogen, or —OH. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁴and R⁷ are each independently halogen or —OH. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁴ and R⁷ are each —OH.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15c) is C₁-C₆ alkyl, aryl, or C₁-C₄ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15c) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(15c) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16c) is hydrogen, C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); whereineach alkyl and aryl is optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16c) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16c) is hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30d) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR¹, —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is independently optionally substituted with one,two, or three R³¹. In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30d) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30d) is independently halogen, —OH, C₁-C₆alkyl, or CI-CG haloalkyl. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30d) is independently halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(30d) is independently halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30d) is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—NR¹R². In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof oneof R¹ or R² is not hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30a).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl),C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a) or—C(═O)₂R^(15a); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(31a).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(15a) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15a) and R^(17a) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(16a) and R^(17a) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate or stereoisomer thereof, R^(16a) and R^(17a) are eachindependently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optimally substituted with one, two, or three R^(30a). Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate a stereoisomer thereof, R¹ isC₁-C₆ alkyl, cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R^(10a). In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is cycloalkyl or C₁-C₆ alkyl(aryl); whereineach alkyl, cycloalkyl, and aryl is independently optionally substitutedwith one, two, or three R^(30a). In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R¹ is cycloalkyl optionally substituted withone, two, or three R^(30a). In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R¹ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30a).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is cycloalkyl optionally substituted with one, two, or three R^(30a). Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30a).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three Rif. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30a) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30a) is independently halogen, or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30a) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²is hydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(III) or (aV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R² is hydrogen. In some embodiments of a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R² is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form an azetidine, a piperidine, a morpholine, or apyrrolidine, each optionally substituted with one, two, or threeR^(30b).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R¹and R² are taken together with the nitrogen atom to which they areattached to form a piperidine optionally substituted with one, two, orthree R^(30b). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R¹ and R² are taken together with the nitrogen atom to whichthey are attached to form a pyrrolidine optionally substituted with one,two, or three R^(30b).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30b) is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or aryl;wherein the alkyl and aryl are optionally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,each R^(30b) is independently aryl optionally substituted with one, two,or three R³¹. In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(30b) is aryl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30b) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30b) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30b) is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30b) is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30b) is independently halogen, or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30b) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—OR⁶⁰.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e), —C(═O)NR^(16e)R^(17e), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate or stereoisomer thereof, R⁶⁰ is —C(═O)R^(15e),—C(═O)OR^(16e), —C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30m).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁰is C₁-C₆ alkyl, cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl),C₁-C₆ alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30m). Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate or stereoisomer thereof, R⁶⁰is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆ alkyl(aryl); wherein each alkyl,cycloalkyl, and aryl is independently optionally substituted with one,two, or three R^(30m). In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁰ is cycloalkyl or C₁-C₆ alkyl(aryl); whereineach alkyl, cycloalkyl, and aryl is independently optionally substitutedwith one, two, or three R^(30m). In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶⁰ is cycloalkyl optionally substituted withone, two, or three R^(30m). In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R⁶⁰ is C₁-C₆ alkyl(aryl); wherein alkyl and arylare independently optionally substituted with one, two, or threeR^(30m).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15e) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15e) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof: R^(15e) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16e) and R^(17c) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(16e) and R^(17e) are eachindependently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16e) and R^(17e) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30m) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30m) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30m) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—SR⁶¹.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶¹is hydrogen, —C(═O)R^(15f), —C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁₋₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate or stereoisomer thereof, R⁶¹ is —C(═O)R^(15f),—C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(acyl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶¹ is C₁-C₆ alkyl, cycloalkyl,C₁-C₆ alkyl(aryl). C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30n). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof: R⁶¹ is C₁-C₆ alkyl, cycloalkyl,or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl isindependently optionally substituted with one, two, or three R^(30n). Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶¹is cycloalkyl or C₁-C₆ alkyl(aryl); wherein each alkyl, cycloalkyl, andaryl is independently optionally substituted with one, two, or threeR^(30n). In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate; or stereoisomer thereof,R⁶¹ is cycloalkyl optionally substituted with one, two, or threeR^(30n). In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R⁶¹ is C₁-C₆ alkyl(aryl); wherein alkyl and aryl are independentlyoptionally substituted with one, two, or three R^(30n).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15f) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15f) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(15f) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16f) and R^(17f) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(16f) and R^(17f) are eachindependently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16f) and R^(17f) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30n) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30n) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30n) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is—CR⁶²R⁶³R⁶⁴.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶²is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(O)OR^(16g), —C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶² is hydrogen, halogen, —CN,—OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),or C₁-C₆ alkyl optionally substituted with one, two, or three R^(30o).In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶¹is hydrogen, halogen, or —OH. In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶² is hydrogen or halogen. In some embodimentsof a compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶² is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶³is hydrogen, halogen, —CN, —OH, —OR^(15g), —NR^(16g)R^(17g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), or C₁-C₆ alkyl optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶³ is hydrogen, halogen, —CN,—OH, —OR^(15g), —NR^(16g)R^(17g), —C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),or C₁-C₆ alkyl optionally substituted with one, two, or three R^(30o).In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶³is hydrogen, halogen, or —OH. In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R⁶³ is hydrogen or halogen. In some embodimentsof a compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶³ is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R⁶⁴is —OR^(15g), —SR^(15g), —S(═O)R^(15g), —NR^(16g)R^(17g),—S(═O)₂R^(15g), —NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g),—C(═O)OR^(16g), —C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶⁴ is —OR^(15g), —SR^(15g), —S(═O)R^(15g), —NR^(16g)R^(17g),—S(═O)₂R^(15g), —NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g),—C(═O)R^(16g), —C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶⁴ is —OR^(15g), —NR^(16g)R^(17s), —C(═O)R^(15g),—C(O)OR^(16g), —C(═O)NR^(16g)R^(17g), cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one, two, orthree R^(30o). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶⁴ is —OR^(15g), —NR^(16g)R^(17g), cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30o). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R⁶⁴ is —OR^(15g) or—NR^(16g)R^(17g). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶⁴ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30o). Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R₆₄is cycloalkyl or heterocycloalkyl; wherein each cycloalkyl andheterocycloalkyl is independently optionally substituted with one, two,or three R^(30o). In some embodiments of a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R⁶⁴ is aryl, or heteroaryl; wherein each aryl, and heteroarylis independently optionally substituted with one, two, or three R^(30o).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15g) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyland aryl is optionally substituted with one, two, or three halogen. Insome embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15g) is C₁-C₆ alkyl or C haloalkyl. In some embodiments of a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R^(15g) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16g) and R^(17g) are each independently hydrogen, C₁-C₆ alkyl, aryl,or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl is optionallysubstituted with one, two, or three halogen. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(16g) and R^(17g) are eachindependently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16g) and R^(17g) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30o) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30o) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30o) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³is halogen, —CN, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R³ is halogen, —CN, —OR^(15b),—NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30c). In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R³ is halogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15b) is C₁-C₆ alkyl optionally substituted with one, two, or threehalogen. In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(15b) is C₁-C₆ alkyl or C₁-C₆ haloalkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(15b) is C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16b) and R^(17b) are each independently hydrogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl optionally substituted with one, two, or three halogen.In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(16b) and R^(17b) are each independently hydrogen or C₁-C₆ alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(18b) is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl). In some embodiments of a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, R^(18b) is cycloalkyl or C₁-C₆alkyl(cycloalkyl).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30c) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30c) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30c) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30c) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are each independently hydrogen, aryl, or—(CR²³R²⁴)_(w)OC(═O)OR²³. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R²¹ and R²² are each hydrogen or—(CR²³R²⁴)_(w)OC(═O)OR²⁵. In some embodiments of a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R²¹ and R²² are each hydrogen. In some embodimentsof a compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R²¹ and R²² are each—(CR²³R²⁴)_(w)OC(═O)OR²⁵.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is1 or 2. In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is2. In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is1.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR²³ and R²⁴ are independently hydrogen, halogen, or C₁-C₆ alkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR²³ and R²⁴ are hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR²⁵ is independently hydrogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R²⁵ is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, R²¹and R²² are taken together with the atoms to which they are attached toform a heterocycloalkyl optionally substituted with one, two, or threeR^(30l). In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R²¹ and R²² are taken together with the atoms to which they are attachedto form a heterocycloalkyl optionally substituted with one, two, orthree R^(30l).

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(30l) is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(30l) is aryl optionally substituted with one, two, or three R³¹.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30l) is independently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R³¹. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30l) is independentlyhalogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30l) is independently halogen or C₁-C₆ alkyl. In some embodiments ofa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R^(30l) is independentlyhalogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30l), R^(30g), R^(30h), R^(30i), R^(30j), and R^(30k) isindependently halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,each R^(30f), R^(30g), R^(30h), R^(30i), R^(30j), and R^(30k) isindependently halogen, —CN, —OH, —OR^(a), C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,each R^(30d) is independently halogen, —OH, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofeach R^(30l), R^(30g), R^(30h), R^(30i), R^(30j), and R^(30k) isindependently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR^(30f), R^(30g), R^(30h), R^(30i), R^(30j), and R^(30k) isindependently halogen, or C₁-C₆ alkyl. In some embodiments of a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, each R^(30f), R^(30g), R^(30h),R^(30i), R^(30j), and R^(30k) is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³¹ is independently halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, eachR³¹ is independently halogen or C₁-C₆ alkyl. In some embodiments of acompound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, each R³¹ is independentlyhalogen. In some embodiments of a compound of Formula (III) or (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,each R³¹ is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(a) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compoundof Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(a) isindependently C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl. In someembodiments of a compound of Formula (I), (OI), (IIa), (IIb), (III), or(IV) or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(a) is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Insome embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(a) is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) is independently hydrogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compoundof Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, each R^(b) isindependently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or cycloalkyl. Insome embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, each R^(b) is independently hydrogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I),(II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof; each R^(b) is independentlyhydrogen or C₁-C₆ alkyl. In some embodiments of a compound of Formula(I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof each R^(b) is hydrogen. In someembodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or(IV) or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, each R^(b) is independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof: R^(c) and R^(d) are each independently hydrogen,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodimentsof a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,R^(c) and R^(d) are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula(I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, R^(c) and R^(d) are eachindependently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or(IV) or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(c) and R^(d) are each independently hydrogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(c) and R^(d) are each hydrogen. In someembodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or(IV) or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(c) and R^(d) are each independently C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(c) and R^(d) are taken together with thenitrogen atom to which they are attached to form a heterocycloalkyloptionally substituted with one, two, or three halogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In some embodiments of a compound of Formula (I), (II),(IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, R^(c) and R^(d) are taken togetherwith the nitrogen atom to which they are attached to form a pyrrolidineoptionally substituted with one, two, or three halogen or C₁-C₆ alkyl.In some embodiments of a compound of Formula (I), (II), (IIa), (IIb),(III), or (IV) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, R^(c) and R^(d) are taken together with thenitrogen atom to which they are attached to form a piperidine optionallysubstituted with one, two, or three halogen or C₁-C₆ alkyl. In someembodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or(IV) or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, R^(c) and R^(d) are taken together with the nitrogen atom towhich they are attached to form a piperazine optionally substituted withone, two, or three halogen or C₁-C₆ alkyl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments is a compound, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, having a structure selectedfrom:

Ex. STRUCTURE NAME  1

(2-(((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]dipyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-2-oxoethyl)phosphonic acid  2

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]dipyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)-2-oxoethyl)phosphonic acid 3

((N-(((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]dipyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfamoyl)methyl)phosphonic acid 4

(2-((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)ethyl)phosphonic acid  5

(2-(((2R,3S,4R,5R)-5-(4- (benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonic acid  6

(2-(((2R,3S,4R,5R)-5-(4- (benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonic acid  7

((((2R,3S,4R,5R)-5-(4- (benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  8

(2-(((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2- oxoethyl)phosphonic acid  9

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)-2-oxoethyl)phosphonic acid  10

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  11

(2-(((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2- oxoethyl)phosphonic acid  12

((((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  13

(((((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)thio)methyl)phosphonic acid  14

(((((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl) methyl)sulfonyl)methyl)phosphonic acid 15

((((2R,3S,4R,5R)-5-(2-chloro-4- ((cyclopropylmethyl)amino)-7H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  16

((((2R,3S,4R,5R)-5-(5-chloro-7- ((cyclopropylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  17

((((2R,3S,4R,5R)-5-(4-((2- chlorobenzyl)amino)-6-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  18

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  19

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxy-3- methyltetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  20

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isobutyl)amino)-2-oxoethyl)phosphonic acid  23

((((1R,2R,3S,4R)-4-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyl)methoxy)methyl) phosphonic acid  24

((((2R,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  25

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  26

((((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  27

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  28

(2-(benzyl(((2R,3S,4R,5R)-5-(6-chloro-4-((3-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  29

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- fluorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  30

((((2R,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  31

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  32

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- (trifluoromethyl)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  33

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  34

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1- (3-chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  35

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)- 1-(3-chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  36

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(3-chlorophenyl)ethyl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  37

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  38

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  39

((((2R,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzyl)(methyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  40

((((2R,3S,4R,5R)-5-(2-chloro-4-((2- chlorobenzyl)amino)-7H-pyrazolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  41

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- methylbenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  42

((((2R,3S,4R,5R)-5-(6-chloro-4- morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  43

((((2R,3S,4R,5R)-5-(6-chloro-4- (ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  44

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  45

((((2R,3S,4R,5R)-5-(6-chloro-4-((((R)-tetrahydrofuran-3-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  46

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- cyanobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  47

((((2R,3S,4R,5R)-5-(6-chloro-4-((2,3-dichlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  48

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1- methyl-1H-indazol-7-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  49

((((2R,3S,4R,5R)-5-(6-chloro-4- ((naphthalen-1-ylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  50

(((S)-1-((2S,3S,4R,5R)-5-(6-chloro-4- ((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  51

((((2R,3S,4R,5R)-5-(6-chloro-4- ((quinolin-5-ylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  52

((((2R,3S,4R,5R)-5-(6-chloro-4- (methylamino)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  53

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentyl(methyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  54

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-isobutoxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  55

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6- (pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  56

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6- (methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  57

((((2R,3S,4R,5R)-5-(4-amino-6- chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  58

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chloro-2-fluorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  59

((((2R,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)(methyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  60

(((R)-1-((2S,3S,4R,5R)-5-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)ethoxy)methyl)phosphonic acid  61

(((((2S,3S,4R,5R)-5-(6-chloro-4-((3-chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid 62

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid  63

((((2R,3S,4R,5R)-5-(6-chloro-4- (isobutylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  64

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  65

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  66

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid  67

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6- (isobutylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  68

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclobutylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  69

((((2R,3S,4R,5R)-5-(6-chloro-4-((((S)-tetrahydrofuran-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  70

((((2R,3S,4R,5R)-5-(6-chloro-4-((((R)-tetrahydrofuran-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  71

((((2R,3S,4R,5R)-5-(6-chloro-4-((((S)-tetrahydrofuran-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  72

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  73

((((2R,3S,4R,5R)-5-(6-chloro-4- ((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  74

((((2R,3S,4R,5R)-5-(6-chloro-4- (isopropylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  75

((((2R,3S,4R,5R)-5-(6-chloro-4- (phenylamino)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  76

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopropylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  77

((((2R,3S,4R,5R)-5-(6-chloro- 4-(((1s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  78

((((2R,3S,4R,5R)-5-(6-chloro-4- (pentan-3-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  79

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclobutylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  80

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)- tetrahydrofuran-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  81

((((2R,3S,4R,5R)-5-(6-chloro-4- (pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  82

((((2R,3S,4R,5R)-5-(4- ((cyclopropylmethyl)amino)-6-methoxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  83

((((2R,3S,4R,5R)-5-(4-(azetidin-1-yl)-6-cyclo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  84

(((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)(methyl)amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)sulfonyl)methyl)phosphonic acid  85

((2-((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)ethoxy)methyl)phosphonic acid  86

((((2R,3S,4R,5R)-5-(6-chloro-4-(((3,3-difluorocyclobutyl)methyl)amino-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  87

((((2R,3S,4R,5R)-5-(6-chloro-4-((3,3- difluorocyclobutyl)amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  88

(((2-((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)ethyl)sulfonyl)methyl)phosphonic acid  89

((((2R,3S,4R,5R)-5-(6-chloro-4- ((((1s,3S)-3-hydroxy-3-methylcyclobutyl)methyl)amino)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  90

((((2R,3S,4R,5R)-5-(6-chloro-4-((pyridin-2-ylmethyl)amino-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid  91

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1- cyclopropylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  92

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1- cyclopropylethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  93

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclohexylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  94

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- cyclopropylethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  95

((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclohexylamino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  96

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1- methylcyclopropyl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  97

((((2R,3S,4R,5R)-5-(2-chloro-4- ((cyclopropylmethyl)amino)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid  98

((N-(((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)-N-methylsulfamoyl)methyl)phosphonic acid  99

((((2R,3S,4R,5R)-5-(6-chloro-4-(N-cyclopentylacetamido)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid 100

((((2R,3S,4R,5R)-5-(6-chloro-4-(5- methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 101

(3-((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)propyl)phosphonicacid 102

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)- 2,2-dimethylcyclopentyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 103

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-2,2- dimethylcyclopentyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 104

((((2R,3S,4R,5R)-5-(6-chloro-4- (((1S,2R)-2-methylcyclopropyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 105

((((2R,3S,4R,5R)-5-(6-chloro-4- (((1S,2R)-2- methylcyclopropyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 106

(((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphoryl) methyl)phosphonic acid 107

(((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclobutylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 108

(((((2S,3S,4R,5R)-5-(6-chloro-7- (cyclobutylamino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 109

(2-((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclobutylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)(methyl)amino)-2- oxoethyl)phosphonic acid 110

(((((2S,3S,4R,5R)-5-(5-chloro-7-(cyclobutylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid111

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclobutylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 112

(((((2S,3S,4R,5R)-5-(2-chloro-6- (cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid113

(((((2S,3S,4R,5R)-5-(5-chloro-7- ((cyclobutylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 114

(((((2S,3S,4R,5R)-5-(5-chloro-7-(((S)-1-(4-fluorophenyl)ethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 115

(2-((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)(methyl)amino)-2- oxoethyl)phosphonic acid 116

(((((2S,3S,4R,5R)-5-(6-chloro-4- (((S)-1-(4-fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid117

(((((2S,3S,4R,5R)-5-(6-chloro-4-((4-fluorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid118

(((((2S,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 119

(((((2S,3S,4R,5R)-5-(5-chloro-7-((4- fluorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 120

(((((2S,3S,4R,5R)-5-(5-chloro-7-((4- chlorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 121

(((((2S,3S,4R,5R)-5-(5-chloro-7-((2,3- dihydro-1H-inden-2-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 122

(((((2S,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzyl)amino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 123

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid124

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclobutylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 125

(((((2S,3S,4R,5R)-5-(4- (cyclopentylamino)-6-(hydroxymethyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid126

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2,3- dihydro-1H-inden-2-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 127

(((((2S,3S,4R,5R)-5-(6-chloro-4-((4- chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 128

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 129

(((((2S,3S,4R,5R)-5-(6-chloro-4- (((S)-1-(2-chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid130

(((((2S,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-2-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 131

(4S)-2-(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclobutylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)-4-(3- chlorophenyl)-1,2,3- dioxaphosphinane2-oxide 132

((((2R,3S,4R,5R)-5-(4- chloropentylamino)- 6-(2-hydroxypropan-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 133

(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclopentyl(2-methoxyethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 134

(((((2S,3S,4R,5R)-5-(6-chloro-4- (((1R,2S)-2-methylcyclopentyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 135

(((((2S,3S,4R,5R)-5-(6-chloro-4- (((1S,2R)-2-methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid136

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((R)- 2,3-dihydro-1H-inden-1-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonic acid 137

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid 138

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1- cyanocyclopropyl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid

In some embodiments is a compound, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, having a structure selectedfrom:

In some embodiments is a compound, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, having a structure selectedfrom:

In some embodiments is a compound, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, having a structure selectedfrom;

Further Forms of Compounds Disclosed Herein Isomers Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds disclosed herein, or a solvate, orstereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H, ³H,¹³C, ¹⁴O, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds described herein, and the metabolites, pharmaceuticallyacceptable salts, esters, prodrugs, solvate, hydrates or derivativesthereof which contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14,i.e., ¹⁴C, isotopes are particularly preferred for their ease ofpreparation and detectability. Further, substitution with heavy isotopessuch as deuterium, i.e., ²H, produces certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. In some embodiments, theisotopically labeled compound or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefor react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid, or inorganic base, such salts including acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfate, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxy benzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylateundeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxyl is acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, and muconic acid.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran, ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulasdescribed herein. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

Preparation of the Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa. Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K), Parish Chemical Co. (Orem Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sander et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modem SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Palk, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons. NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J, and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera. J. (editor) “Modem Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai. S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomans, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0: Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2:“Industrial Organic Chemicals: Starting Materials and Intermediates; AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29635-X,in 8 volumes; “Organic Reactions” (1942-200) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference for the preparation and selection ofpharmaceutical salts of the compounds described herein is P. H. Stahl &C. G. Wemuth “Handbook of Pharmaceutical Salts”, Verlag HelveticaChimica Acta, Zurich, 2002.

In some embodiments, the compounds described herein are prepared asoutlined in Schemes 1-9.

Pharmaceutical Compositions

In certain embodiments, the compound disclosed herein is administered asa pure chemical. In some embodiments, the compound disclosed herein iscombined with a pharmaceutically suitable or acceptable carrier (alsoreferred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, or steroisomer thereof, together with one or morepharmaceutically acceptable carriers. The carrier(s) (or excipient(s))is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound disclosed herein,or a pharmaceutically acceptable salt, solvate, or steroisomer thereof.

In certain embodiments, the compound disclosed herein is substantiallypure, in that it contains less than about 5%, or less than about 1%, orless than about 0.1%, of other organic small molecules, such asunreacted intermediates or synthesis by-products that are created, forexample, in one or more of the steps of a synthesis method.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Methods of Treatment

The compounds disclosed herein, or a pharmaceutically acceptable salt,solvate, or steroisomer thereof, are useful as inhibitors of CD73 and,therefore, useful in the treatment of diseases or disorders in which itis believed CD73 activity plays a role. In some embodiments, the diseaseor disorder is cancer. In some embodiments, the disease or disorder isan infection. In some embodiments, the disease or disorder is aneurodegenerative disease. In some embodiments, the disease or disorderis a psychiatric disorder.

Disclosed herein are methods of treating a subject with a disordermediated by CD73 comprising the step of administering to the subject aneffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof.

Cancer

CD73 has been found to be overexpressed in many cancer cell lines andtumor types including breast cancer, colorectal cancer, ovarian cancer,gastric cancer, and gallbladder cancer and associated with poorprognosis. Increasing evidence suggests that CD73 is a key proteinmolecule in cancer development.

Higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, resistance to chemotherapy andmetastasis, and with shorter patient survival time in cancer. In someembodiments, the compounds disclosed herein are useful in reducing tumorneovascularization, invasiveness, resistance to chemotherapy andmetastasis, as well as to lengthen patient survival time in cancerpatients. In some embodiments, the CD73 inhibitors disclosed herein areused to control tumor neovascularization, progression, resistance tochemotherapy, and metastasis.

One embodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a compound of disclosedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof.

In some embodiments, the cancer is chemoresistant cancer, radioresistant cancer, anti-hormonal therapy resistant cancer, or treatmentrefractory cancer. In some embodiments, the cancer is relapsed cancer,persistent cancer, or recurrent cancer. Another embodiment providedherein describes a method of reducing incidences of cancer recurrence.Also provided here in some embodiments, is a method for treating atherapy-resistant cancer. In some embodiments, the cancer is metastasiccancer.

In certain embodiments, the cancer treatable with the methods providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia, or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML); (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, non-secretory myeloma osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease: (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondresarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, aligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mutinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including but not limited to, pheochromocytom and adrenocorticalcarcinoma; (14) thyroid cancer, including, but not limited to, papillaryor follicular thyroid cancer, medullary thyroid cancer, and anaplasticthyroid cancer; (15) pancreatic cancer, including, but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; (16) pituitary cancer,including, but limited to, Cushing's disease, prol actin-secretingtumor, acromegaly, and diabetes insipius; (17) eye cancer, including,but not limited, to ocular melanoma such as iris melanoma, choroidalmelanoma, and cilliary body melanoma, and retinoblastoma: (18) vaginalcancer, including, but not limited to, squamous cell carcinoma,adenocarcinoma, and melanoma; (19) vulvar cancer, including, but notlimited to, squamous cell carcinoma, melanoma, adenocarcinoma, basalcell carcinoma, sarcoma, and Paget's disease; (20) cervical cancers,including, but not limited to, squamous cell carcinoma, andadenocarcinoma; (21) uterine cancer, including, but not limited to,endometrial carcinoma and uterine sarcoma; (22) ovarian cancer,including, but not limited to, ovarian epithelial carcinoma, borderlinetumor, germ cell tumor, and stromal tumor; (23) esophageal cancer,including, but not limited to, squamous cancer, adenocarcinoma, adenoidcystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma,sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell(small cell) carcinoma; (24) stomach cancer, including, but not limitedto, adenocarcinoma, fungating (polypoid), ulcerating, superficialspreading, diffusely spreading, malignant lymphoma, liposarcoma,fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer;(27) liver cancer, including, but not limited to, hepatocellularcarcinoma and hepatoblastoma; (28) gallbladder cancer, including, butnot limited to, adenocarcinoma; (29) cholangiocarcinomas, including, butnot limited to, pappillary, nodular, and diffuse; (30) lung cancer,including, but not limited to, non-small cell lung cancer, squamous cellcarcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma,and small-cell lung cancer; (31) testicular cancer, including, but notlimited to, germinal tumor, seminoma, anaplastic, classic (typical),spermatocytic, nonserninoma, embryonal carcinoma, teratoma carcinoma,and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including,but not limited to, adenocarcinoma, leiomyosarcoma, andrhabdomyosarcorna; (33) penal cancer; (34) oral cancer, including, butnot limited to, squamous cell carcinoma; (35) basal cancer; (36)salivary gland cancer, including, but not limited to, adenocarcinoma,mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynxcancer, including, but not limited to, squamous cell cancer andverrucous; (38) skin cancer, including, but not limited to, basal cellcarcinoma, squamous cell carcinoma and melanoma, superficial spreadingmelanoma, nodular melanoma, lentigo malignant melanoma, and acrallentiginous melanoma; (39) kidney cancer, including, but not limited to,renal cell cancer, adenocarcinoma, hypemephroma, fibrosarcoma, andtransitional cell cancer (renal pelvis and/or uterer); (40) Wilms'tumor, (41) bladder cancer, including, but not limited to, transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; (42) reproductive cancers, such as cervical cancer,uterus cancer, ovarian cancer, or testicular cancer; (43) esophaguscancer; (44) laryngeal cancer; (45) head and neck cancers (includingmouth, nose, throat, larynx, sinuses, or salivary glands cancers); andother cancer, including, not limited to, myxosarcoma, osteogenicsarcoma, endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, and papillary adenocarcinomas (SeeFishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions: The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America).

In certain embodiments, the cancer treatable with the methods providedherein is a hematological malignancy. In certain embodiments, thehematological malignancy is a T-cell malignancy. In certain embodiments,T-cell malignancies include peripheral T-cell lymphoma not otherwisespecified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblasticlymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma(ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma,hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasalNUT-cell lymphomas, or treatment-related T-cell lymphomas.

In certain embodiments, the hematological malignancy is a B-cellmalignancy. In certain embodiments, B-cell malignancies include acutelymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), acute monocytic leukemia (AMoL), chroniclymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocyticlymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia,multiple myeloma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, Burkitfs lymphoma, non-Burkitt high gradeB cell lymphoma, primary mediastinal B-cell lymphoma (PMBL),immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, Bcell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, or lymphomatoid granulomatosis. In certainembodiments, the B-cell malignancy is diffuse large B-cell lymphoma(DLBCL). In certain embodiments, the DLBCL is an activated B-cell DLBCL(ABC-DLBCL), a germinal center B-cell like DLBCL (GBC-DLBCL), a doublehit DLBCL (DH-DLBCL), or a triple hit DLBCL (TH-DLBCL).

In certain embodiments, the cancer treatable with the methods providedherein is lung cancer, melanoma, breast cancer, ovarian cancer,colorectal cancer, gastric cancer, gallbladder cancer, or prostatecancer.

Infections

A number of studies have shown changes in the activity of the CD39/CD73axis during infections induced by a variety of microorganisms. Oneembodiment provides a method of treating an infection in a subject inneed thereof, comprising administering to the subject a compound ofdisclosed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.

In some embodiments, the infection is a viral infection, a bacterialinfection, or a parasitic infection.

Parasitic Infections

In some embodiments, the infection is a parasitic infection. In someembodiments, the parasitic infection is caused by infection of thesubject with a protozoan organism. In some embodiments, the protozoanorganism selected from the group consisting of the genera Acanthamoeba,Babesia, Balantidium, Cryptosporidium, Dientamoeba, Eimeria, Entamoeba,Giardia, Isospora, Leishmania, Naegleria, Neospora, Plasmodium,Sarcocystis, Theileria, Toxoplasma, Trichomonas, Trypanosoma, or anycombinations thereof. In some embodiments, the parasitic infection iscaused by an infection with Toxoplasma gondii (T. gondii). In someembodiments, the parasitic infection is toxoplasmosis. In someembodiments, the toxoplasmosis is acute toxoplasmosis, latenttoxoplasmosis, or cutaneous toxoplasmosis.

Acute toxoplasmosis: acute toxoplasmosis is often asymptomatic inhealthy adults. However, symptoms may manifest and are ofteninfluenza-like: swollen lymph nodes, headaches, fever, fatigue, ormuscle aches and pains that last for a month or more. Rarely will ahuman with a fully functioning immune system develop severe symptomsfollowing infection. People with weakened immune systems are likely toexperience headache, confusion, poor coordination, seizures, lungproblems that may resemble tuberculosis or Pneumocystis jirovecipneumonia (a common opportunistic infection that occurs in people withAIDS), or blurred vision caused by severe inflammation of the retina(ocular toxoplasmosis). Young children and immunocompromised people,such as those with HIV/AIDS, those taking certain types of chemotherapy,or those who have recently received an organ transplant, may developsevere toxoplasmosis. In some instances, toxoplasmosis causes damage tothe brain (encephalitis) or the eyes (necrotizing retinochoroiditis).Infants infected via placental transmission may be born with either ofthese problems, or with nasal malformations, although thesecomplications are rare in newborns. The toxoplasmic trophozoites causingacute toxoplasmosis are referred to as tachyzoites, and are typicallyfound in bodily fluids.

Latent toxoplasmosis: due to its asymptomatic nature, it is easy for ahost to become infected with Toxoplasma gondii and develop toxoplasmosiswithout knowing it. Although mild, flu-like symptoms occasionally occurduring the first few weeks following exposure, infection with T. gondiiproduces no readily observable symptoms in healthy human adults. In mostimmunocompetent people, the infection enters a latent phase, duringwhich only bradyzoites (tissue cysts) are present; these tissue cystsand even lesions can occur in the retinas, alveolar lining of the lungs(where an acute infection may mimic a Pneumocystis jirovecii infection),heart, skeletal muscle, and the central nervous system (CNS), includingthe brain. Cysts form in the CNS (brain tissue) upon infection with T.gondii and persist for the lifetime of the host. Most infants who areinfected while in the womb have no symptoms at birth, but may developsymptoms later in life.

Cutaneous toxoplasmosis: in some embodiments, skin lesions occur in theacquired form of the disease, including roseola and erythemamultiforme-like eruptions, prurigo-like nodules, urticaria, andmaculopapular lesions. Newborns may have punctate macules or ecchymoses.Diagnosis of cutaneous toxoplasmosis is based on the tachyzoite form ofT. gondii being found in the epidermis.

Viral Infections

In some embodiments, the infection is a viral infection. In certainembodiments, the viral infection treatable with the methods providedherein includes, but is not limited to, chickenpox, the flu (influenza),herpes, human immunodeficiency virus (HIV/AIDS), human papillomavirus(HPV), Infectious mononucleosis, mumps, measles, rubella, shingles,viral gastroenteritis (stomach flu), viral hepatitis, viral meningitis,and viral pneumonia.

Neurodegenerative Diseases

In the central nervous system, adenosine plays a critical role incontrolling a multitude of neural functions. Through the activation ofP1 receptors, adenosine is involved in diverse physiological andpathological processes such as regulation of sleep, general arousalstate and activity, local neuronal excitability, and coupling of thecerebral blood flow to the energy demand. In some embodiments, themanipulation of adenosine production via CD73 inhibitors has therapeuticpotential in neurodegenerative diseases. One embodiment provides amethod of treating a neurodegenerative disease in a subject in needthereof, comprising administering to the subject a compound of disclosedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof. In certain embodiments, the neurodegenerative disease treatablewith the methods provided herein includes, but is not limited to,Alzheimer's disease, Parkinson's disease, and Huntington's disease. Oneembodiment provides a method of treating a psychiatric disorder in asubject in need thereof, comprising administering to the subject acompound of disclosed herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof. In some embodiments, the psychiatricdisorder is schizophrenia or autism.

Combination Therapy

In certain instances, the compound disclosed herein, or apharmaceutically acceptable salt, solvate, or steroisomer thereof, isadministered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by a patient is increasedby administering one of the compounds described herein with a secondtherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit.

In one specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt, solvate, or steroisomer thereof, isco-administered with a second therapeutic agent, wherein the compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orsteroisomer thereof, and the second therapeutic agent modulate differentaspects of the disease, disorder or condition being treated, therebyproviding a greater overall benefit than administration of eithertherapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simplyadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulating apharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with a secondtherapeutic agent. Therapeutically-effective dosages of drugs and otheragents for use in combination treatment regimens are optionallydetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orsteroisomer thereof, is initiated prior to, during, or after treatmentwith a second agent described herein, and continues until any timeduring treatment with the second agent or after termination of treatmentwith the second agent. It also includes treatments in which a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate, orsteroisomer thereof, and the second agent being used in combination areadministered simultaneously or at different times and/or at decreasingor increasing intervals during the treatment period. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g., the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated, and so forth. In additional embodiments, whenco-administered with a second therapeutic agent, the compound providedherein is administered either simultaneously with the second therapeuticagent, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds disclosed herein, or a pharmaceutically acceptable salt,solvate, or steroisomer thereof, as well as combination therapies, areadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound varies. Thus, in one embodiment, the compounds described hereinare used as a prophylactic and are administered continuously to subjectswith a propensity to develop conditions or diseases in order to preventthe occurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

In certain embodiments, the second therapeutic agent is an adjuvant. Incertain embodiments, the second therapeutic agent is an anti-canceragent. In certain embodiments, the second therapeutic agent is anantiemetic. In certain embodiments, the second therapeutic agent is ananti-infective agent. In certain embodiments, the second therapeuticagent is an antiviral agent. In certain embodiments, the secondtherapeutic agent is an antibacterial agent.

In some embodiments, the compound disclosed herein, or apharmaceutically acceptable salt, solvate, or steroisomer thereof, isadministered in combination with an adjuvant. In one embodiment, thetherapeutic effectiveness of one of the compounds described herein isenhanced by administration of an adjuvant (i.e., by itself the adjuvanthas minimal therapeutic benefit, but in combination with anothertherapeutic agent, the overall therapeutic benefit to the patient isenhanced).

In some embodiments, the compound disclosed herein, or apharmaceutically acceptable salt, solvate, or steroisomer thereof, isadministered in combination with an anti-cancer agent.

In some embodiments, the anti-cancer agent is a hormone blockingtherapy. Hormone blocking therapy includes the use of agents that blockthe production of estrogens or block the estrogen receptors. In someembodiments, hormone blocking therapy includes the use of estrogenreceptor modulators and/aromatase inhibitors. Estrogen receptormodulators include triphenylethylene derivatives (e.g., tamoxifen,toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (aphosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (acarboxylic acid derivative of tamoxifen)); non-steroidal estrogenreceptor modulators (e.g., raloxifene, LY353381 (SERM3) and LY357489);steroidal estrogen receptor modulators (e.g., ICI-182.780). Aromataseinhibitors include steroidal aromatase inhibitors and non-steroidalaromatase inhibitors. Steroidal aromatase inhibitors include, but arenot limited to, exemestane. Non-steroidal aromatase inhibitors include,but are not limited to, anastrozole and letrozole.

In certain embodiments, compounds disclosed herein are used incombination with one or more passive immunotherapies, including but notlimited to, naked monoclonal antibody drugs and conjugated monoclonalantibody drugs. Examples of naked monoclonal antibody drugs that can beused include, but are not limited to, rituximab, an antibody against theCD20 antigen; trastuzumab, an antibody against the HER2 protein;alemtuzumab, an antibody against the CD52 antigen: cetuximab, anantibody against the EGFR protein; and bevacizumab which is ananti-angiogenesis inhibitor of VEGF protein.

Examples of conjugated monoclonal antibodies include, but are notlimited to, radiolabeled antibody ibritumomab tiuxetan; radiolabeledantibody tositumomab; and immunotoxin gemtuzumab ozogamicin whichcontains calicheamicin: BL22, an anti-CD22 monoclonalantibody-immunotoxin conjugate; radiolabeled antibodies such asOncoScint (Registered trademark) and ProstaScint (Registered trademark):brentuximab vedotin; and ado-trastuzumab emtansine.

Further examples of therapeutic antibodies that can be used include, butare not limited to, abciximab, an antibody against the glycoproteinIIb/IIIa receptor on platelets; daclizumab, an immunosuppressive,humanized anti-CD25 monoclonal antibody; edrecolomab, a murineanti-17-IA cell surface antigen igG2a antibody; BEC2, a murineanti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFRIgG antibody; VITAXIN (Registered Trademark) a humanized anti-aVbeta 3integrin antibody; Campath 1H/LDP-03, a humanized anti CD52 IgG1antibody; Smart M195, a humanized anti-CD33 IgG antibody; epratuzumab, ahumanized anti-CD22 IgG antibody; Lymphoscan; visilizumab; CM3, ahumanized anti-ICAM3 antibody; IDEC-114 a primatized anti-CD80 antibody;IDEC-131 a humanized anti-CD40L antibody; IDEC-151 a primatized anti-CD4antibody; IDEC-152 a primatized anti-CD23 antibody; SMART anti-CD3, ahumanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5)antibody; D2E7, a humanized anti-TNF-alpha antibody; CDP870, a humanizedanti-TNF-alpha Fab fragment; IDEC-151, a primatized anti-CD4 IgG1antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptdavidin(+biotin-yttrium 90); CDP571, a humanized anti-TNF-alpha IgG4 antibody;LDP-02, a humanized anti-alpha 4beta 7 antibody; OrthoClone OKT4A, ahumanized anti-CD4 IgG antibody; ANTOVA (Registered Trademark), ahumanized anti-CD40L IgG antibody; ANTEGREN (Registered Trademark), ahumanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-beta 2antibody.

In some embodiments, the second therapeutic agent for use in combinationwith a compound disclosed herein, or a pharmaceutically acceptable salt,solvate, or steroisomer thereof, include one or more of the following:abiraterone; abarelix; adriamycin; actinomycin; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; alemtuzumab;allopurinol: alitretinoin; altretamine; ambomycin: ametantrone acetate;aminoglutethimide; aminolevulinic acid; amifostine; amsacrine;anastrozole: anthramycin: aprepitant: arsenic trioxide: asparaginase:asperlin: azacitidine; azetepa; azotomycin; batimastat; bendamustinehydrochloride; benzodepa; bevacizumab; bexarotene; bicalutamide;bisantrene hydrochloride; bi snail de dimesylate: bizelesin; bleomycin;bleomycin sulfate; bortezomib; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer, carboplatin;carmustine; carubicin hydrochloride; carzelesin; capecitabine;cedefingol; cetuximab; chlorambucil; cirolemycin; cisplatin: cladribine;clofarabine: crisnatol mesylate; cyclophosphamide; cytarabine:dacarbazine; dasatinib; daunorubicin hydrochloride; dactinomycin;darbepoetin alfa; decitabine; degarelix; denileukin diftitox;dexormaplatin; dexrazoxane hydrochloride; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate: duazomycin;edatrexate: eflomithine hydrochloride; elsamitrucin; eltrombopagolamine: enloplatin; enpromate: epipropidine: epirubicin hydrochloride:epoetin alfa: erbulozole: erlotinib hydrochloride; esorubicinhydrochloride: estramustine: estramustine phosphate sodium: etanidazole;etoposide; etoposide phosphate; etoprine; everolimus; exemestane;fadrozole hydrochloride; fazarabine; fenretinide; filgrastim:floxuridine; fludarabine phosphate: fluorouracil; fluorocitabine;fosquidone; fostriecin sodium; fulvestrant; gefitinib: gemcitabine;gemcitabine hydrochloride; gemcitabine cisplatin; gemtuzumab ozogamicin;goserelin acetate; histrelin acetate; hydroxyurea: idarubicinhydrochloride; ifosfamide; iimofosine; ibritumomab tiuxetan; idarubicin;ifosfamide: imatinib mesylate; imiquimod; interleukin I1 (includingrecombinant interleukin IL or rlL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a;interferon gamma-1b: iproplatin; irinotecan hydrochloride; ixabepilone;lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolideacetate; leucovorin calcium; leuprolide acetate; levamisole; liposomalcytarabine; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium;methoxsalen; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;mitogillin; mitomalcin; mitomycin C; mitosper; mitotane; mitoxantronehydrochloride; mycophendic acid; nandrolone phenpropionate; nelarabine;nilotinib; nocodazoie; nofetumomab; nogalamycin; ofatumuntb; oprelvekin;ormaplatin; oxaliplatin; oxisuran; paclitaxel; palifermin; palonosetronhydrochloride; pamidronate; pegfilgrastim; pemetrexed di sodium;pentostatin; panitumumab; pazopanib hydrochloride; pemetrexed disodium;plerixafor; pralatrexate; pegaspargase; peliomycin; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; quinacrine; raloxifene hydrochloride;rasburicase; recombinant HPV bivalent vaccine; recombinant HPVquadrivalent vaccine; riboprine; rogletimide; rituximab; romidepsin;romiplostim; safingol; safingol hydrochloride; sargramostim; semustine;simtrazene; sipuleucel-T; sorafenib; sparfosate sodium; sparsomycin;spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;streptozocin; sulofenur; sunitinib malate; talisomycin; tamoxifencitrate; tecogalan sodium; tegafur; teloxantrone hydrochloride;temozolomide; temoporfin; temsirolinus; teniposide; teroxirone;testolactone; thalidomide; thiamiprine; thioguanine; thiotepa;tiazofunn; tirapazamine; topotecan hydrochloride; toremifene;tositumomab and I 131 Iodine tositumomab; trastuzumab; trestoloneacetate; tretinoin; tricinbine phosphate; trimetrexate; trimetrexateglucuronate; triptorelin; tubuiozole hydrochloride; uracil mustard;uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastinesulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidinesulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbinetartrate; vinrosidine sulfate; vinzolidine sulfate; vorinostat;vorozole; zeniplatin; zinostatin; zoledronic acid; and zorubicinhydrochloride.

In some embodiments, the second therapeutic agent is an alkylatingagent. Examples of alkylating agents for use in combination with acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or steroisomer thereof, include, but are not limited to,nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.).

Other agents that are optionally used in the methods and compositionsdescribed herein for the treatment or prevention of cancer includeplatinum coordination complexes (e.g., cisplatin, carbobiatin),anthracenedione (e.g., mitoxantrone), substituted urea (e.g.,hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

In some embodiments, the second therapeutic agent is an immunotherapyagent. Examples of immunotherapy agents for use in combination with acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, or steroisomer thereof, include, but are not limited to,checkpoint inhibitors (e.g., anti-PD1 and anti-PD-L1 inhibitors), cancervaccines (e.g., sipuleucel-T), oncolytic viruses (e.g., talimogenelaherparepvec), cytokines (e.g., IL-2 and INF-alpha), CAR-T cells.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or steroisomer thereof, is used in combinationwith anti-emetic agents to treat nausea or emesis, which results fromthe use of a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, or steroisomer thereof, anti-cancer agent(s) and/orradiation therapy. Anti-emetic agents include, but are not limited to:neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such asondansetron, granisetron, tropisetron, palonosetron, and zatisetron),GABAB receptor agonists (such as baclofen), corticosteroids (such asdexamethasone, prednisone, prednisolone, or others), dopamineantagonists (such as, but not limited to, domperidone, droperidol,haloperidol, chlorpromazine, promethazine, prochlorperazine,metoclopramide), antihistamines (H1 histamine receptor antagonists, suchas but not limited to, cyclizine, diphenhydramine, dimenhydrinate,meclizine, promethazine, hydroxyzine), cannabinoids (such as but notlimited to, cannabis, marinol, dronabinol), and others (such as, but notlimited to, trimethobenzamide; ginger, emetrol, propofol).

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or steroisomer thereof, is used in combinationwith an agent useful in the treatment of anemia. Such an anemiatreatment agent is, for example, a continuous eythropoiesis receptoractivator (such as epoetin-α).

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or steroisomer thereof, is used in combinationwith an agent useful in the treatment of neutropenia. Examples of agentsuseful in the treatment of neutropenia include, but are not limited to,a hematopoietic growth factor which regulates the production andfunction of neutrophils such as a human granulocyte colony stimulatingfactor, (G-CSF). Examples of a G-CSF include filgrastim.

In one embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or steroisomer thereof, is administered to amammal in combination with a non-steroidal anti-inflammatory drug(NSAID). NSAIDs include, but are not limited to: aspirin, salicylicacid, gentisic acid, choline magnesium salicylate, choline salicylate,choline magnesium salicylate, choline salicylate, magnesium salicylate,sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofencalcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac,ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac,indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium,mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (suchas, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib,etoricoxib, lumiracoxib, CS-502, TIE-522 L-745 337, and NS398).

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt, solvate, or steroisomer thereof, is used in combinationwith radiation therapy (or radiotherapy). Radiation therapy is thetreatment of cancer and other diseases with ionizing radiation.Radiation therapy is optionally used to treat localized solid tumors,such as cancers of the skin, tongue, larynx, brain, breast, prostate,colon uterus, and/or cervix. It is also optionally used to treatleukemia and lymphoma (cancers of the blood-forming cells and lymphaticsystem, respectively).

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (MC) wereperformed on silica gel unless otherwise noted.

Example 1.(2-(((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-oxoethyl)phosphonicAcid (1)

Step A.(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diylDiacetate (1a)

β-D-Ribofuranose 1,2,3,5-tetraacetate (5.73 g, 18.0 mmol) was heated at90° C. for 10 min, 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.5 g,18.0 mmol) and SnCl₄ (60 mg) was added successively. After the mixturewas heated at 130° C. for 15 min under reduced pressure, it was cooledto rt, diluted with water and extracted with DCM. The combined organicswere washed with water, brine, dried, and concentrated. The residue waspurified by column chromatography (petroleum ether/ethyl acetate: 10:1to 5:1) to give the title compound (1a) (2.4 g, 68% yield) as a yellowsolid.

Step B.(2R,3R,4R,5R)-2-(Acetoxymethyl)-S-(6-chloro-4-(2-chlorobenzylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diylDiacetate (1b)

A mixture of 1a (2.4 g, 5.37 mmol), (2-chlorophenyl)methanamine (912 mg,6.44 mmol), trimethylamine (813 mg) and EtOH (40 mL) was heated at 50°C. for 1 h. The mixture was cooled to rt and concentrated. The residuewas purified by column chromatography (petroleum ether/ethyl acetate:5:1) to provide the title compound (1b) (1.7 g, 58% yield) as a yellowsolid.

Step C.(2R,3R,4S,5R)-2-(6-Chloro-4-(2-chlorobenzylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(1c)

A mixture of 1b (240 mg, 3.8 mmol), SnO(n-Bu)₂ (3.07 g, 12.3 mmol) andmethanol (40 ml) was heated at 65° C. overnight. The mixture was cooledto rt and concentrated. The residue was purified by columnchromatography (DCM/MeOH: 50:1 to 20:1) to give the title compound (1c)(1.0 g. 77% yield).

Step D.((3aR,4R,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolol-[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(1d)

To a solution of(2R,3R,4S,5R)-2-[6-chloro-4-[(2-chlorophenyl)methylamino]pyrazolo[3,4-d]pyrimidin-1-yl]-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(1c) (3.00 g, 7.04 mmol) in DMF (32 mL) was added 2,2-dimethoxypropane(2.59 mL, 21.1 mmol) followed by p-toluenesulfonic acid monohydrate (268mg, 1.41 mmol). The mixture was heated to 70° C. for 1 h. The reactionmixture was cooled to rt and concentrated. The residue was purified bycolumn chromatography (SiO₂, 0-100% EtOAc/hexanes) to give the titlecompound (1d) (2.79 g. 85% yield) as a white solid.

Step E.((3aR,4R,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl2-(diethoxyphosphoryl)acetate (1e)

To a slurry of((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(1d) (100 mg, 0.21 mmol) and diethoxyphosphoryl acetic acid (0.07 mL,0.43 mmol) in DCM (2 mL) was added dicyclohexylcarbodiimide (88 mg, 0.43mmol) and 4-dimethylaminopyridine (1.3 mg, 0.010 mmol). The reactionmixture was allowed to stir overnight. The reaction mixture was filteredover Celite and the filtrate was concentrated. The residue was purifiedby column chromatography (SiO₂, 0-100% EtOAc/hexanes) to provide thetitle compound (1e) (118 mg, 85% yield) as a white solid.

Step F.(2-(((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-oxoethyl)phosphonicAcid (1)

To a solution of((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl2-(diethoxyphosphoryl)acetate (1e) (118 mg, 0.18 mmol) in DCM (6.5 mL)was added bromo(trimethyl)silane (0.14 mL, 1.1 mmol) at rt. The mixturewas stirred overnight. The reactions was concentrated and dissolved inMeOH (5 mL). The mixture was stirred for 30 min and was thenconcentrated again. The residue was dissolved in hexafluoro-2-propanol(2.3 mL) and water (0.11 mL) and hydrochloric acid (2 M in dioxane, 0.11mL, 0.44 mmol) was added dropwise. After the mixture was stirred for 1h, it was quenched with sat. NH₄OH (0.3 mL) and was concentrated. Theresidue was purified by reverse phase HPLC (C18 column, 0 to 65%acetonitrile/water with 0.1% TFA) to provide the title compound (1) as awhite solid in the TFA salt form (43 mg, 35% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 9.32 (t, J=5.55 Hz, 1H), 8.30 (s, 1H), 7.47-7.56 (m, 1H),7.41-7.47 (m, 1H), 7.31-7.38 (m, 2H), 6.05 (d, J=3.51 Hz, 1H), 5.49-5.62(br s, 1H), 4.77 (d, J=5.55 Hz, 2H), 4.50 (t, J=4.0 Hz, 1H), 4.26-4.37(m, 2H), 4.05-4.11 (m, 1H), 3.92-3.99 (m, 1H), 2.76-2.81 (m, 2H), m/z(ESI, +ve ion)=548.0 [M+H]⁺.

Example 2.(2-((((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-oxoethyl)phosphonicAcid (2)

Step A.1-((3aR,4R,6R,6aR)-6-(Azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-chloro-N-(2-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(2a)

To a solution of((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4yl)methanol (1d) (228 mg, 0.49 mmol) in THF (2.3 mL) was addedtriphenylphosphine (154 mg, 0.59 mmol) and DIAD (0.12 mL, 0.59 mmol)dropwise. The reaction mixture was cooled to 0° C., and stirred for 10min before diphenyl phosphorazidate (0.13 mL, 0.59 mmol) was addeddropwise. The mixture was warmed to rt overnight. The mixture wasconcentrated and the resulting residue was purified by columnchromatography (SiO₂, 0-100% EtOAc/hexanes) to provide the titlecompound (2a) (144 mg, 60% yield) as a foamy solid.

Step B.1-((3aR,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-chloro-N-(2-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(2b)

To a solution of1-((3aR,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-chloro-N-(2-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(2a) (144 mg, 0.29 mmol) in pyridine (3 mL) was added triphenylphosphine(115 mg, 0.44 mmol). After the mixture was stirred for 2 h, sat. NH₄OH(7 mL) was added and the mixture was allowed to stir overnight. Thereaction mixture was concentrated and the residue was purified by columnchromatography (SiC₂, 0-10% MeOH/DCM with 0.1% TEA) to provide the titlecompound (2b) (130 mg, 95% yield) as a white solid.

Step C. Diethyl(2-((((3aR,4R,6R,6aR)-6-(6-chloro-44(2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2-oxoethyl)phosphonate(2c)

To a solution of1-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-chloro-N-(2-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(2b) (130 mg, 0.28 mmol) and diethoxyphosphorylacetic acid (0.09 mL,0.56 mmol) in DCM (3 mL) was added dicyclohexylcarbodiimide (115 mg,0.56 mmol) and 4-dimethylaminopyridine (1.7 mg, 0.01 mmol). The mixturewas allowed to stir overnight. The reaction mixture was filtered throughCelite and the filtrate was concentrated. The resulting residue waspurified by column chromatography (SiO₂, 0-6% MeOH/DCM) to provide thetitle compound (2c) (120 mg, 67% yield) as a white solid.

Step D.(2-((((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-oxoethyl)phosphonicacid (2)

To solution of diethyl(2-((((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2-oxoethyl)phosphonate(2c) (120 mg, 0.19 mmol) in DCM (6.5 mL) was addedbromo(trimethyl)silane (0.15 mL, 1.1 mmol) and the mixture was stirredovernight. The reaction mixture was concentrated and the residue wasdissolved in 5 mL MeOH. After 30 min, the mixture was concentrated. Theresidue was dissolved in hexafluoro-2-propanol (2.34 mL) and water (0.11mL) and hydrochloric acid (2M in dioxane, 0.11 mL, 0.45 mmol) was addeddropwise. After the mixture was stirred for 1 h, it was quenched withsat. NH₄OH (0.3 mL). The mixture was concentrated. The residue waspurified by reverse phase HPLC (C18 column, 0 to 65% gradient ofacetonitrile and water with 0.1% TFA) to provide the product (2) (34 mg,28% yield) as a white solid in the TFA salt form. ¹H NMR (400 MHz,DMSO-d6) δ ppm 9.29-9.34 (m, 1H), 8.32 (s, 1H), 7.84-7.90 (m, 1H),7.47-7.53 (m, 1H), 7.40-7.47 (m, 1H), 7.30-7.39 (m, 2H), 6.03 (d, J=3.95Hz, 1H), 5.33-5.51 (br s, 1H), 4.77 (d, J=5.55 Hz, 2H), 4.54 (t, J=4.40Hz, 1H), 4.20 (t, J=4.80 Hz, 1H), 3.85-3.98 (m, 1H), 3.42-3.58 (m, 1H),3.00-3.13 (m, 1H), 2.54-2.64 (m, 2H), m/z (ESI, +ve ion)=547.1 [M+H]⁺.

Example 3.((N-(((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfamoyl)methyl)phosphonicAcid (3)

Step A.N-(((3aR,4R,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)methanesulfonamide(3a)

To a solution of1-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3](dioxol-4-yl)-6-chloro-N-(2-chlorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(2b) (250 mg, 0.54 mmol) in DCM (2.5 mL) was added triethylamine (0.22mL, 1.6 mmol) followed by addition of methanesulfonyl chloride (0.05 mL,0.64 mmd) and 4-dimethylaminopyridine (13 mg, 0.11 mmd). The mixture wasallowed to stir overnight. The reaction mixture was concentrated and theresidue was purified by column chromatography (SiO₂, 0-6% MeOH/DCM) toprovide the product (3a) (242 mg, 83% yield) as a white solid.

Step B. Diethyl((N-(((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl)methyl)phosphonate(3b)

To a solution of diisopropylamine (0.11 mL, 0.79 mmd) in THE (3 mL) at−78° C. was added n-butyllithium (1.6 M in hexanes, 0.46 mL, 0.73 mmol)over 5 min. The solution slowly warmed to 0° C. over 30 min and themixture was cooled to −78° C. To the reaction mixture was addedN-(((3aR,4R,6R⁶aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-13.1)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)methanesulfonamide(3a) (120 mg, 0.22 mmol) dissolved in THF (2 mL) dropwise over 5 min.The mixture allowed to stir for 30 min at −78° C. Diethylchlorophosphate (0.04 mL, 0.24 mmol) was added dropwise and the mixturewas allowed to stir for 15 min. The solution was slowly warmed to 0° C.over 1 h. The reaction mixture was quenched with sat. NH₄C₁ (1.0 mL) andwas partitioned between EtOAc (25 mL) and water (25 mL). The aqueouslayer was extracted two additional times with EtOAc (25 mL) and thecombined organic layers were dried with MgSO₄, filtered, andconcentrated. The resulting residue was purified by columnchromatography (SiO₂, 20-100% EtOAc/hexanes) to provide the product (3b)(36 mg, 24% yield) as a white solid.

Step C.((N-(((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfamoyl)methyl)phosphonicAcid (3)

To solution of diethyl((N-(((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl)methyl)phosphonate(3b) (36 mg, 0.05 mmol) in DCM (2 mL) was added bromo(trimethyl)silane(0.04 mL, 0.32 mmol) and the mixture was allowed to stir overnight. Thereaction mixture was concentrated and dissolved in MeOH (5 mL). After 30min, the mixture was concentrated. The residue was dissolved inhexafluoro-2-propanol (0.67 mL) and water (0.03 mL) followed byhydrochloric acid (2 M in dioxane, 0.03 mL, 0.13 mmol). After themixture was stirred for 1 h, it was quenched with sat. NH₄OH (1 mL) andconcentrated. The residue was purified by reverse phase HPLC (C18column, 0 to 65% acetonitrile/water with 0.1% TFA) to provide theproduct (3) (13 mg, 31% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 9.31-9.35 (m, 1H), 8.31 (s, 1H), 7.47-7.57 (m, 1H),7.39-7.47 (m, 1H), 7.30-7.39 (m, 2H), 6.96-7.01 (m, 1H), 6.03 (d, J=4.40Hz. 1H), 5.35-5.56 (br s, 1H), 4.77 (d, J=5.20 Hz, 2H), 4.56 (t, J=4.60Hz, 1H), 4.23 (t, J=4.40 Hz, 1H), 3.89-4.02 (m, 1H), 3.43-3.56 (m, 2H),3.20-3.32 (m, 1H), 3.03-3.17 (m, 1H), m/z (ESI, +ve ion)=583.0 [M+H]⁺.

Example 4. (2-((2R,3S,4R,5R)-5-(6-Chloro-4(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)ethyl)phosphonicAcid (4)

Step A.(3aR,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde(4a)

Oxalyl chloride (10.4 g) was added dropwise to a solution of DMSO (7.5g) in DCM (100 ml) at −78° C. After the resulting solution was stirredfor 15 min, a solution of((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(15.2 g) in DCM (20 ml) was added dropwise. The reaction mixture wasstirred for 20 min at −78° C. DIPEA (48 g) was added and the mixture wasstirred at −78° C. for another 30 min, then allowed to warm to rt for 2h. The solution was quenched with water and extracted with DCM. Theorganic layer was dried, concentrated to afford the title compound (4a)(10 g, 66% yield) as a yellow liquid.

Step B. Diethyl((E)-2-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)phosphonate(4b)

Tetraethyl methylenediphosphonate was (500 mg, 1.74 mmol) was added topotassium tert-butoxide solution (1 M in THF, 20 ml) at 0° C., and thereaction mixture was stirred for 10 min, then warm to rt. After beingstirred at rt for another 30 min, the reaction was cooled to 0° C., and4a (174 mg, 0.87 mmol) was added. The mixture was then stirred at 0° C.for 1 h and quenched with sat. NH₄Cl (1.0 mL). The aqueous layer wasextracted with EtOAc and the combined organic layers were dried withMgSO₄, filtered, and concentrated. The residue was purified by columnchromatography to provide the title compound (4b) (211 mg, 25% yield).

Step C. Diethyl(2-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl)phosphonate(4c)

Palladium on carbon (10% wt, 100 mg) was added to a solution of 4b (700mg) in MeOH (20 ml). After the mixture was stirred under hydrogen (1atm) for 2 h, it was filtered and filtrate was concentrated to affordthe title compound (4c) (640 mg, 92% yield) as a crude oil.

Step D. Diethyl(2-((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)ethyl)phosphonate(4d)

A solution of 4c (4.0 g, 11.83 mmol) in sulfuric acid (0.1 N, 40 mL) anddioxane (16 mL) was refluxed for 2 h. After the reaction was cooled tort, it was adjusted to PH-7 and concentrated to dryness. The residue wasevaporated with pyridine twice to afford the crude product (3.4 g),which was used in the next step without purification.

Step E.(3R,4R,5R)-5-(2-(Diethoxyphosphoryl)ethyl)tetrahydrofuran-2,3,4-triyltriacetate (4e)

To a solution of 4d (3.4 g, 11.83 mmol) in dry pyridine (45 mL) wasadded dropwise acetic anhydride (6.8 g, 66.7 mmol) at 0° C. After thereaction mixture was stirred at rt overnight, it was concentrated todryness. The residue was treated with EtOAc (100 mL)/water (100 mL) andthe organic layer was separated, washed with brine (50 mL), dried, andconcentrated. The residue was purified by column chromatography (SiO₂,33% EtOAc/petroleum) to afford the title compound (4e) (3.2 g, 66% yieldover two steps).

Step F.(2R,3R,4R,5R)-2-(4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(2-(diethoxyphosphoryl)ethyl)tetrahydrofuran-3,4-diyldiacetate(4f)

To a solution of 4e (2 g, 4.88 mmol),4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (922 mg, 4.88 mmol), andTMSOTf (4.33 g, 19.6 mmol) in dry MeCN (60 mL) was added dropwise DBU(2.24 g, 14.7 mmol). The mixture was stirred at rt for 2 h and waspoured into sat. aq. NaHCO₃ and the solution was extracted with EtOAc.The organic layer was washed with brine, dried, and concentrated invacuo. The residue was purified by column chromatography (SiO₂, 50%EtOAc petroleum) to afford the title compound (4f) (1.4 g, 53% yield).

Step G.(2R,3R,4R,5R)-2-(6-Chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(2-(diethoxyphosphoryl)ethyl)tetrahydrofuran-3,4-diylDiacetate (4 g)

A mixture of 4f (1.4 g, 2.6 mmol),(S)—N-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (477 mg, 2.6mmol) and TEA (656 mg, 6.5 mmol) in ethanol (40 mL) was stirred at 55°C. for 1 h and then concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, 25% EtOAc/petroleum) to afford the titlecompound (4g) (912 mg, 54% yield).

Step H.(2-((2R,3S,4R,5R)-5-(6-Chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)ethyl)phosphonicAcid (4)

To a solution of 4 g (230 mg, 0.35 mmol) and TEA (1.43 g, 14.16 mmol) indry MeCN (25 mL) was added bromo(trimethyl)silane (1.62 g, 10.6 mmol).After the reaction mixture was stirred at rt overnight, it wasconcentrated to dryness. The residue was treated with methanol (3 mL)and 1 N NaOH (3 mL) and the mixture was stirred overnight at rt. Thesolution was directly purified by reverse phase HPLC (C18 column, 0 to65% acetonitrile/water with 0.1% TFA) to afford the title compound (4)(30 mg, 14% yield) as a TFA salt. ¹H NMR (400 MHz; D₂O) δ 8.14 (m, 1H),7.22-7.02 (m, 4H), 5.90 (m, 1H), 5.04 (m, 1H), 4.33-4.09 (m, 2H),3.99-3.87 (m, 1H), 2.97-2.76 (m, 5H), 2.55-2.34 (m, 1H), 2.1-1.92 (m,1H), 1.72-1.70 (m, 2H), 1.27 (m, 2H), m/z (ESI, +ve ion)=510.3 [M+H]⁺.

Examples 5.(2-(((2R,3S,4R,5R)-5-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonicAcid (5)

Step A. Diethyl(2-(((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)ethyl)phosphonate(5a)

Cesium carbonate (830 mg, 2.55 mmol) was added to a mixture of((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(26 g, 12.7 mmol) and diethyl vinylphosphonate (2 g, 12.7 mmol). Afterthe mixture was stirred at 50° C. overnight, it was directly purified bycolumn chromatography (SiO₂, 50% EtOAc/petroleum ether) to afford thetitle compound (5a) (2.36 g, 50% yield).

Step B.(3R,4R,5R)-5-((2-(Diethoxyphosphoryl)ethoxy)methyltetrahydrofuran-2,3,4-triylTriacetate (5b)

Concentrated sulfuric acid (0.72 mL) was added dropwise to a solution of5a (1.3 g, 3.53 mmol) in acetic acid (3 mL) and acetic anhydride (2.14mL) at 0° C. The mixture was allowed to stir at rt overnight and pouredinto aq. NaHCO₃. The solution was extracted with EtOAc and the organiclayer was washed with brine, dried and concentrated. The residue waspurified by column chromatography (SiO₂, 100% EtOAc) to afford the titlecompound (5b) (520 mg, 33% yield) as a mixture of two diastereomers.

Step C.(3R,4R,5R)-2-(4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((2-(diethoxyphosphoryl)ethoxy)methyl)tetrahydrofuran-3,4-diylDiacetate (5c)

TMSOTf (1.04 g, 4.72 mmol) and DBU (532 mg, 3.54 mmol) were added to asolution of 5b (520 mg, 1.18 mmol) and4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (220 mg, 1.18 mmol) in MeCN(14 mL) successively. After the reaction mixture was stirred at rt for 2h, it was poured into sat.aq. NaHCO₃ and extracted with EtOAc. Theorganic layer was washed with brine, dried and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, 33%EtOAc/petroleum ether) to afford the title compound (5c) (250 mg, 38%yield) as a mixture of two diastereomers.

Step D.(3R,4R,5R)-2-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((2-(diethoxyphosphoryl)ethoxy)methyl)tetrahydrofuran-3,4-diylDiacetate (5d)

A mixture of 5c (250 mg, 0.44 mmol), Et₃N (58 mg, 0.53 mmol) andN-methyl-1-phenylmethanamine (70 mg, 0.53 mmol) in EtOH (8 mL) wasstirred at 55° C. for 1 h. The mixture was then concentrated in vacuoand purified by column chromatography (SiO₂, 25% EtOAc/petroleum ether)to afford the title compound (5d) (200 mg, 70% yield).

Step E. Diethyl (2-(((2R,3S,4R,5R)5-(4-(benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonate(5e-1) and Diethyl(2-(((2R,3S,4R,5S)-5-(4-(benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonate(5e-2)

To a solution of 5d (200 mg, 0.306 mmol) in methanol (8 mL) was addedpotassium carbonate (220 mg, 0.917 mmol). After the reaction mixture wasstirred at 40° C. for 30 min, it was concentrated in vacuo and theresidue was purified by column chromatography (SiO₂, 100% EtOAc) toafford the crude product as a mixture of two diastereomers (110 mg, 63%yield), which was separated by reverse phase HPLC (C18 column, 0 to 65%acetonitrile/water with 0.1% TFA) to afford 5e-1 (50 mg) and 5e-2 (50mg), respectively.

Step F.(2-(((2R,3S,4R,5R)-5-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonicAcid (5)

To a solution of 5e-1 (50 mg, 0.088 mmol) and TEA (354 mg, 3.51 mmol) indry MeCN (4 mL) was added bromo(trimethyl)silane (403 mg, 2.63 mmol).After the mixture was stirred at rt overnight, it was concentrated invacuo and the residue was purified by reverse phase HPLC (C18 column, 0to 65% acetonitrile/water with 0.1% TFA) to afford title compound (5)(34 mg, 61% yield) as a TFA salt. ¹H NMR (400 MHz, 1320) S 8.14-7.7 (m,1H), 7.25-7.20 (m, 5H), 5.93 (m, 1H), 4.87 (m, 2H), 4.65-4.4 (m, 1H),4.07-4.01 (m, 2H), 3.65-3.52 (m, 4H), 3.25-3.20 (m, 3H), 1.65-1.61 (m,2H), m/z (ESI, +ve ion)=514.3 [M+H]⁺.

Example 6.(2-(((2R,3S,4R,5S)-5-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)ethyl)phosphonicAcid (6)

Compound 6 was prepared from 5e-2 (Example 5, Step E) by proceduresimilar to that described in Example 5, Step F. ¹H NMR (400 MHz, D₂O) S7.74-7.46 (m, 1H), 6.96-6.87 (m, 5H), 5.98 (s, 1H), 4.58-4.37 (m, 3H),4.19-3.99 (m, 2H), 3.66-3.42 (m, 4H), 2.88 (br s, 3H), 1.89-1.85 (m,2H). m/z (ESI, +ve ion)=514.5 [M+H]⁺.

Example 7. ((((2R,3S,4R,5R)5-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (7)

Step A.((3aR,4R,6R,6aR)-6-(4-(benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(7a)

The starting material 7a was prepared from(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate (1a) (Example 1, Step A) by procedures similar to thosedescribed in Example 1, Steps B, C and D, substituting benzylmethylaminefor 2-chlorobenzylamine in Step B.

Step B. Diethyl((((3aR,4R,6R,6aR)-6-(4-(benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1.3]dioxol-4-yl)methoxy)methyl)phosphonate(7b)

To a solution of 7a (300 mg, 0.67 mmol) in dry DMF (10 mL) was addedsodium hydride (60% in mineral oil. 80 mg, 2.02 mmol) at 0° C. Themixture was stirred for 10 min at the same temperature and(diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (433 mg, 1.34 mind)was added. After the reaction mixture was stirred at rt overnight, itwas poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, 33% EtOAc/petroleumether) to afford the title compound (7b) (200 mg, 50% yield).

Step C.((((2R,3S,4R,5R)-5-(4-(Benzyl(methyl)amino)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (7)

To a solution of 7b (140 mg, 0.235 mmol) and TEA (951 mg, 9.41 mmol) indry MeCN (6 mL) was added bromo(trimethyl)silane (1.08 g, 7.06 mmol) andthe mixture was stirred at rt overnight. The mixture was concentrated invacuo and the residue was treated with aq. TFA (50% aqueous solution, 6mL). Alter the mixture was stirred for 1 h, it was concentrated and theresidue was purified by reverse phase HPLC (C18 column, 0 to 65%acetonitrile/water with 0.1% TFA) to afford the title compound (7) (20mg, 14% yield) as a TFA salt. ¹H NMR (400 MHz, D₂O) δ 8.17-7.71 (m, 1H),7.27-7.21 (m, 5H), 5.98 (br s, 1H), 4.95 (m, 2H), 4.25-4.10 (m, 2H),3.70-3.53 (m, 2H), 3.38-3.16 (m, 6H), m/z (ESI, +ve ion)=500.5 [M+H]⁺.

Example 8.(2-(((2R,3S,4R,5R)-5-(6-Chloro-4-(((S)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-oxoethyl)phosphonicAcid (8)

Example 8 was prepared from(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate (1a) (Example 1, Step A) by procedures similar to thosedescribed in Example 1, Steps B, C, D, E and F, substituting(S)—N-methyl-2,3-dihydro-1H-inden-1-amine for 2-chlorobenzylamine inStep B. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.36-8.56 (m, 1H), 7.07-7.40 (m,4H), 6.62 (t, J=8.19 Hz, 1H), 6.08-6.15 (m, 1H), 4.52 (t, J=4.40 Hz,1H), 4.37 (t, J=5.19 Hz, 1H), 4.23-4.31 (m, 1H), 4.07-4.14 (m, 1H),3.93-4.02 (m, 1H), 3.02-3.08 (m, 3H), 2.93-3.02 (m, 1H), 2.84 (brs, 1H),2.70-2.65 (m, 2H), 2.41-2.44 (m, 1H), 2.02-2.07 (m, 1H).

The following examples were made according to the procedures describedin Examples 1-8 using the appropriate starting material.

Ex. LC-MS  9 561.01 [M + H]⁺ 10  520.1 [M + H]⁺ 11  555.0 [M + H]⁺ 12 511.1 [M − H]⁻

Example 13. (((((2S,3S,4R,5R)5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio)methyl)phosphonicAcid (13)

Step A.S-(((3aS,4S,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (13a)

To a dried flask charged with (E)-diisopropyl azodicarboxylate (0.46 mL,2.4 mmol) and THE (12 mL) was added triphenylphosphine (619 mg, 2.36mmol) at 0° C. After the mixture was stirred for 5 min,[(3aR,4R,6R,6aR)-4-[6-chloro-4-[(2-chlorophenyl)methylamino]pyrazolo[3,4-d]pyrimidin-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-1-yl]methanol(1d) (500 mg, 1.07 mmol) and thioacetic acid (0.17 mL, 2.4 mmol) wereadded successively. The mixture was stirred overnight and slowly allowedto warm to rt. The mixture was quenched with TEA (0.1 mL) andconcentrated. The residue was partitioned between EtOAc and water.Aqueous layer was extracted (EtOAc) and combined organic layers weredried (MgSO₄) and concentrated. The residue was purified by flash columnchromatography (SiO₂. 0-100% EtOAc/hexanes, gradient elution) to givethe title compound (13a). The crude product was used in the next stepwithout further purification. m/z (ESI, +ve ion)=524.0 [M+H]⁺.

Step B. ((3aS,4S,6R,6aR)-6-(6-Chloro-4((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanethiol(13b)

To a flask containing 13a (562 mg, 1.07 mmol) was added methanol (24mL), triethylamine (1.69 mL, 12.1 mmol), followed by addition ofDL-dithiothreitol (165 mg, 1.07 mmol). After the mixture was stirred atrt for 3 h, it was concentrated. The residue was purified by flashcolumn chromatography (SiO₂, 0-50% EtOAc/hexanes, a gradient elution) toprovide the title compound (13b) (505 mg, 97.6%). ¹H NMR (400 MHz,Chloroform-d) δ 8.19-7.22 (m, 5H), 6.48 (s, 2H), 5.39-5.20 (m, 1H),5.04-4.80 (m, 3H), 4.24 (td, J=7.05, 1.97 Hz, 1H), 2.71 (t, J=7.31 Hz,2H), 1.56 (s, 3H), 1.47 (t, J=8.48 Hz: 1H), 1.36 (s, 3H), m/z (ESI, +veion)=482.0 [M+H]⁺.

Step C. Di-tert-butyl(((((3aS,4S,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)phosphonate(13c)

To an oven dried flask was added sodium hydride (60% dispersion inmineral oil, 41.9 mg, 1.05 mmol) and 4 mL of DMF. At −10° C., a solutionof 13b (505 mg, 1.05 mmol) in DMF (6 mL) was added. 30 min later, asolution of ditert-butoxyphosphorylmethyl trifluoromethanesulfonate*(410 mg, 1.15 mmol) in DMF (1 mL) was added. The mixture was allowed towarm tort and stirred for 1 h, it was quenched (sat. ammonium chloride)and extracted (EtOAc). The organic layer was dried (MgSO₄), andconcentrated. The residue was purified by flash column chromatography(SiO₂, 30-10% EtOAc/hexanes, a gradient elution) to provide the titlecompound (13c) (500 mg, 69.4% yield). ¹H NMR (400 MHz. Chloroform-d) δ7.86-7.19 (m, 6H), 6.46 (d, J=1.46 Hz, 1H), 5.23 (s, 1H), 4.93-4.80 (m,3H), 4.33-4.28 (m, 1H), 2.81 (d, J=7.60 Hz, 2H), 2.62-2.44 (m, 2H), 1.52(s, 3H), 1.40 (s, 9H), 1.38 (s, 9H), 1.30 (s, 3H), m/z (ESI, +veion)=686.2 [M+H]⁺.

*Synthesis of Ditert-butoxyphosphorylmethyl Trifluoromethanesulfonate

Step 1. To an oven dried flask was added di-t-butyl phosphite (3.24 mL,16 mmol) and water (1 mL) followed by addition of triethylamine (2.68mL, 19.22 mmol) and formaldehyde (37% aqueous solution, 1.2 mL, 16mmol). After the mixture was stirred overnight, it was co-evaporatedthree times with MeOH (10 mL) and one time with DCM (10 mL). Theresulting white solid (3.5 g) was placed under high vacuum for 30 min.The crude product was used in the next step without furtherpurification.

Step 2. The crude ditert-butoxyphosphorylmethanol (3.5 g, 15.61 mmol) inthe original flask was dissolved in anhydrous DCM (50 mL). To thereaction mixture was added 2,6-lutidine (3.64 mL, 31.2 mmol) and theflask was cooled to −78° C. Using a syringe pump, triflic anhydride(2.83 mL, 17.3 mmol) was added dropwise over 30 min. After the mixturewas warmed to 0° C., and stirred for 3 h, it was cooled to −78° C., andthen diluted with Et₂O (100 mL). The solids were filtered over Celiteand the filtrate was partitioned with water (75 mL). The solution wasextracted (Et₂O) and the combined organics were washed (water andbrine), dried (MgSO₄), filtered, and concentrated to provideditert-butoxyphosphorylmethyl trifluoromethanesulfonate (4.6 g, 12.9mmol, 83%) as a red oil.

Step D.(((((2S,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thiomethyl)phosphonicAcid (13)

To an oven dried flask was added 13c (82 mg, 0.12 mmol) andhexafluoro-2-propanol (1.48 mL) followed by addition of water (0.07 mL,4 mmol) and hydrochloric acid (4 M in dioxane, 0.07 mL, 0.29 mmol).After the mixture was stirred at rt for 25 min, it was quenched (sat.ammonium hydroxide) and concentrated. The residue was dissolved in MeOH(1 mL) and DMF (1 mL), filtered through a syringe filter. The solutionwas purified by reverse preparative HPLC (0-65% ACN/H₂O with 0.1% TFA)to afford the title compound (13) (41 mg, 0.063 mmol, 53%) as atrifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (t, J=5.55Hz, 1H), 8.30 (s, 1H), 7.54-7.47 (m, 1H), 7.46-7.40 (m, 1H), 7.37-7.28(m, 2H), 6.02 (d, J=4.24 Hz, 1H), 4.77 (d, J=5.55 Hz; 2H), 4.57 (t,J=4.80 Hz, 1H), 4.21 (t, J=4.80 Hz, 1H), 4.09-3.99 (m, 1H), 3.02-2.90(m, 1H), 2.87-2.76 (m, 1H), 2.64-2.53 (m, 2H), m/z (ESI, +ve ion)=536.0[M+H]⁺.

Example 14.(((((2S,3S,4R,5R)-5(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicAcid (14)

Step A. Di-tert-Butyl(((((3aS,4S,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfonyl)methyl)phosphonate(14a)

To an oven dried flask was added 13c (235 mg, 0.34 mmol) followed byaddition of MeOH (2 mL), water (2 mL), and THE (4.0 mL). To this mixturewas added potassium peroxymonosulfate (519 mg, 3.41 mmol). After themixture was stirred at rt for 24 h, it was quenched (sat. sodiumbicarbonate) and extracted (EtOAc). The combined organic layers weredried (MgSO₄), and concentrated. The crude product (14a) was used in thenext step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ 9.34(t, J=5.63 Hz, 1H), 8.32 (s, 1H), 7.54-7.48 (m, 1H), 7.47-7.42 (m, 1H),7.37-7.31 (m, 2H), 6.06 (d, J=3.51 Hz, 1H), 4.77 (d, J=5.85 Hz; 2H),4.48 (t, J=4.09, 1H), 4.40-4.28 (m, 2H), 3.74-3.56 (m, 4H), m/z (ESI,+ve ion)=718.2 [M+H]⁺.

Step B.(((((2S,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)methyl)phosphonicAcid (14)

To a flask was added 14a (246 mg, 0.34 mmol) and hexafluoro-2-propanol(4.24 mL, 40.3 mmol) followed by addition of water (0.2 mL, 11 mmol) andhydrochloric acid (4 M in dioxane, 0.2 mL, 0.82 mmol). After the mixturewas stirred for 25 min, it was quenched with sat. ammonium hydroxide(0.2 mL) and concentrated. The residue was dissolved in DMF (6 mL) andpurified by reverse preparative HPLC (0-65% ACN/H₂O with 0.1% TFA) toprovide the title compound (14) (127 mg, 0.224 mmol). ¹H NMR (400 MHz,DMSO-d6) δ 9.34 (t, J=5.63 Hz, 1H), 8.32 (s, 1H), 7.54-7.48 (m, 1H),7.47-7.42 (m, 1H), 7.37-7.31 (m, 2H), 6.06 (d, J=3.51 Hz, 1H), 4.77 (d,J=5.85 Hz, 2H), 4.48 (t, J=4.09, 1H), 4.40-4.28 (m, 2H), 3.74-3.56 (m,4H), m/z (ESI, +ve ion)=568.0 [M+H]⁺.

Example 15.((((2R,3S,4R,5R)-5-(2-Chloro-4-((cyclopropylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (15)

Step A.(3aR,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(15a)

Concentrated sulfuric acid (0.3 mL) was added to a suspension ofD-ribose (12.5 g, 83 mmol) in acetone (125 mL). The mixture was stirredat rt for 90 min to a clear solution which was neutralized withsaturated aqueous sodium carbonate. The solution was filtered overCelite and the filtrate was concentrated to afford the crude product (16g), which was used in next step without purification.

Step B.((3aR,4R,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (15b)

To a solution of 15a (16 g, 83 mmol) in pyridine (60 mL) was addeddropwise BzCl (12.9 g, 91 mmol) at 0° C. After the reaction was stirredat rt overnight, it was concentrated and the residue was diluted (EtOAc)and washed (5% aq. citric acid). The organic layer was dried andconcentrated and the residue was purified by flash column chromatography(SiO₂, 20% EtOAc/petroleum ether) to provide the title compound (15b)(12 g, 49% yield for the two steps), m/z (ESI, +ve ion)=316.4 [M+Na]⁺.

Step C.((3aR,4R,6aR)-6-Bromo-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (15c)

To a solution of 15b (2 g, 6.8 mmol) in dry DCM (60 mL) was addeddropwise TMSBr (2.1 g, 13.6 mmol) at 0° C. After the mixture was allowedto warm to rt and stirred for 2 h, it was concentrated at rt and theresidue was used in next step immediately.

Step D. ((3aR,4R,6R,6aR)-6-(2-Chloro-4((cyclopropylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylbenzoate (15d)

To a suspension of2-chloro-N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1g, 4.9 mmol) in dry MeCN (30 mL) was added sodium hydride (60%dispersion in mineral oil, 314 mg, 7.4 mmol) at rt. After the reactionwas stirred at rt for 30 min, a solution of 15c (6.8 mmol) in dry MeCN(10 mL) was added. The mixture was stirred at rt overnight and thenpoured into sat. NH₄Cl. The solution was extracted (EtOAc) and theorganic layer was washed (brine), dried, and concentrated. The residuewas purified by flash column chromatography (SiO₂, 15% EtOAc/petroleumether) to provide the title compound (15d) (600 mg, 1.21 mmol, 30%), m/z(ESI, +ve ion)=521 [M+Na]⁺.

Step E. ((3aR,4R,6R,6aR)-6-(2-Chloro4-((cyclopropylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]diazol-4-yl)methanol(15e)

To a solution of 15d (600 mg, 1.2 mmol) in methanol (17 mL) was addedK₂CO₃ (166 mg, 1.2 mmol) at rt. After the mixture was stirred at 40° C.for 0.5 h, it was concentrated and the residue was purified by flashcolumn chromatography (SiO₂, 33% EtOAc/petroleum ether) to provide thetitle compound (15e) (400 mg, 1.01 mmol, 83%), m/z (ESI, +ve ion)=395.1[M+H]⁺.

Step F.((((2R,3S,4R,5R)-5-(2-Chloro-4-((cyclopropylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (15)

The title compound was prepared from((3aR,4R,6R,6aR)-2-chloro-4-((cyclopropylmethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(15e) by procedures similar to those described in Example 17, Steps Gand H. m/z (ESI, +ve ion)=448.8 [M+H]⁺.

Example 16.((((2R,3S,4R,5R)-5-(5-Chloro-7-((cyclopropylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (16)

Step A. 2,6-Dichloro-5-nitropyrimidin-4-amine (16a)

To a solution of 2,4,6-trichloro-5-nitropyrimidine (9.0 g, 39.4 mmol) inTHE (540 mL) was added an ammonia solution (10.8 mL, 10 N in EtOH, 78.8mmol) dropwise at −70° C. After the reaction was stirred at −70° C. for30 min, it was acidified with AcOH (pH 4-5) and concentrated. Theresidue was diluted with EtOAc and the resulting mixture was stirred for30 min and filtered. The solids were washed with EtOAc and the organicswere combined and concentrated to afford the title compound (16a) (8.0g, 97%), which was directly used for the next step without furtherpurification.

Step B. 2,6-Dichloropyrimidine-4,5-diamine (16b)

A mixture of iron powder (10.7 g, 191 mmol), acetic acid (24 ml) andethanol (30 mL) was heated at 55° C. for 0.5 h. A solution of 16a (8.0g, 38.3 mmol) in ethanol (50 ml) was added dropwise. After the mixturewas stirred at 55° C. for 20 min, it was cooled to rt and filtered. Thefiltrate was concentrated, the residue was diluted with water and thesolution extracted with EtOAc. The combined organics were washed withwater and brine, dried and concentrated. The residue was purified bycolumn chromatography (petroleum ether/ethyl acetate: from 5:1 to 3:1)to give the title compound (161)) (4.4 g, 60.4%) as a white solid.

Step C. 5,7-Dichloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (16c)

A suspension of 2,6-dichloropyrimidine-4,5-diamine (16b) (4.4 g, 24.58mmol) in water (47 ml) was heated and the solid was dissolved. Thesolution was cooled to 0° C., and acetic acid (94 ml) was added,followed by addition of a solution of sodium nitrite (3.05 g, 44.3 mmol)in water (47 mL) during a period of 15 min. The reaction mixture wasstirred at 0° C. for another 20 min and then was extracted with EtOAc.The organics were neutralized, dried and concentrated, the crude productwas purified by column chromatography (petroleum ether/ethyl acetate:from 3:1 to 2:1) to provide the title compound (16c) (3.4 g, 72.8%) as ayellow solid.

Step D.(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(5,7-dichloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3,4-diylDiacetate (16d)

β-D-Ribofuranose 1,2,3,5-tetraacetate (5.73 g, 18.0 mmol) was heated at90° C.; for 10 min before 16c (3.4 g, 18.0 mmol) and SnCl₄ (105 mg) wereadded. After the mixture was heated at 130° C. for 15 min, it was cooledto rt, diluted with water, extracted with DCM. The combined organicswere washed with water and brine, dried and concentrated. The residuewas purified by column chromatography on silica gel (petroleumether/ethyl acetate: from 8:1 to 5:1) to afford crude product, which waspurified by Supercritical Fluid Chromatography (SFC) to give the titlecompound (16d) (4.0 g. 51% yield) as a yellow solid.

Step E.((3aR,4R,6R,6aR)-6-(5-Chloro-7-((cyclopropylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(16e)

The title compound was prepared from(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(5,7-dichloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3yl)tetrahydrofuran-3,4-diyl diacetate (16d) by procedures similar tothose described in Example 1. Steps B, C, and D.

Step F.((((2R,3S,4R,5R)-5-(5-Chloro-7-((cyclopropylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (16)

The title compound was prepared from((3aR,4R,6R,6aR)-6-(5-chloro-7-((cyclopropylmethyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methanol(16e) by procedures similar to those described in Example 17, Steps Gand H. ¹H NMR (400 MHz, D₂O). δ 5.90 (s, 1H), 4.71 (s, 1H), 4.33 (t,J=4.8 Hz, 1H), 4.03 (d, J=2.4 Hz, 1H), 3.54 (d, J=2.4 Hz, 1H), 3.52 (m,1H), 3.33 (d, J=8.4 Hz, 2H), 3.06 (m, 2H), 0.85 (m, 1H), 0.26 (m, 2H),0.00 (m, 2H), m/z (EST, +ve ion)=449.2 [M−H]⁻.

Example 17.((((2R,3S,4R,5R)-5-(4-((2-Chlorobenzyl)amino)-6-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (17)

Step A.((3aR,4R,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (17a)

To a solution of 2-chlorobenzyl analog of 1d (2.8 g, 6.0 mmol) in DCM(60 mL) was added Et₂N (1.5 g, 15 mmol), DMAP (36 mg, 0.3 mmol), andBzCl (0.84 mL, 7.2 mmol) successively at rt. After the mixture wasstirred at rt overnight, it was washed (water, saturated aqueous NaHCO₃,and brine). The organic phase was dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel to give the title compound (17a) (2.4 g, 4.23 mmol, 71%). ¹HNMR (400 MHz, D₂O) δ 6.28-5.90 (m, 1H), 4.71 (s, 1H), 4.32 (t, J=4.8 Hz,1H), 4.04-4.03 (m, 1H), 3.55-3.52 (m, 1H), 3.46 (t, J=6.0 Hz; 1H), 3.33(d, J=7.8 Hz, 2H), 3.05 (d, J=7.2 Hz, 2H), 0.85-0.84 (m, 1H), 0.26-0.24(m, 2H), 0.00 (m, 2H), m/z (ESI, +ve ion)=569.1 [M+H]⁺.

Step B.((3aR,4R,6R,6aR)-6-(4-((2-Chlorobenzyl)amino-6-((E)-styryl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (17b)

17a (2.2 g, 3.9 mmol), phenylvinylboronic acid (1.2 g, 7.8 mmol), andsodium carbonate (1.2 g, 11.7 mmol) were suspended in THF/H₂O (3:1, 40mL). The mixture was degassed by N₂ three times. Subsequently Ph(PPh₃)₄(0.48 g, 0.42 mmol) was added and the mixture was degassed for another 5min. After the mixture was stirred at reflex for 20 h, it was cooled tort and filtered. The filtrate was extracted (EtOAc) and the organiclayers was washed (brine), dried (Na₂SO₄), and concentrated. The residuewas purified by column chromatography to afford the title compound (17b)(1.8 g, 73%) as a yellow solid. m/z (ESI, +ve ion)=637.2 [M+H]⁺.

Step C.((3aR,4R,6R,6aR)-6-(44(2-Chlorobenzyl)amino)-6-formyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (17c)

17b (2.25 g, 3.5 mmol), NaIO₄ (4.5 g, 21.0 mmol), and 2,6-lutidine (0.75g, 7.0 mmol) were suspended in THE/H₂O (2:1, 60 mL). Subsequentlypotassium osmate dehydrate (33 mg, 0.09 mmol) was added. After theresulting mixture was stirred at rt for 20 h, it was quenched (water)and the solution was extracted (EtOAc). The organic layers was washed(water and brine), dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified by column chromatography to affordthe title compound (17c) (1.4 g, 70%) as a yellow solid. m/z (ESI, +veion)=563.2 [M+H]⁺.

Step D.((3aR,4R,6R,6aR)-6-(4-((2-Chlorobenzyl)amino)-6-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylBenzoate (17d)

To a solution of 17c (0.5 g, 0.9 mmol) in MeOH (10 mL) was added NaBH₄(50 mg, 1.35 mmol). After the mixture was stirred at rt for 1.5 h, itwas quenched with water. The solution was extracted (EtOAc). The organiclayers were washed (brine), dried (Na₂SO₄), and concentrated underreduced pressure. The residue was purified by column chromatography toafford the title compound (17d) (340 mg, 74%) as a white solid. m/z(ESI, +ve ion)=565.2 [M+H]⁺.

Step E.((3aR,4R,6R,6aR)-6-(4-((2-Chlorobenzyl)amino)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]diozol-4-yl)methylBenzoate (17e)

To a solution of 17d (400 mg, 0.7 mmol) in DCM (15 mL) was added3,4-dihydro-2H-pyran (1.78 g, 21 mmol) and PPTS (0.18 g, 0.7 mmol). Themixture was stirred at rt overnight and additional 3,4-dihydro-2H-pyran(1.78 g, 21 mmol) and PPTS (0.18 g, 0.7 mmol) were added. After themixture was stirred at rt for two days, it was quenched (water) andextracted (DCM). The organic layers were washed (brine), dried (Na₂SO₄)and concentrated under reduced pressure to afford the title compound(17e) (0.5 g, 100%) as a yellow solid. The crude product was useddirectly without further purification. m/z (ESI, +ve ion)=649.2 [M+H]⁺.

Step F.((3aR,4R,6R,6aR)-6-(4-((2-Chlorobenzyl)amino)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]diozol-4-yl)methanol(171)

A mixture of 17e (340 mg, 0.5 mmol) and K₂CO₃ (217 mg, 2.1 mmol) in MeOH(8 mL) was stirred at rt for 30 min. AcOH (190 mg 4.2 mmol) was addedand the resulting mixture was concentrated in vacuo and the residue waspurified by column chromatography to afford the title compound (17f)(260 mg, 91%) as a white solid. m/z (ESI, +ve ion)=545.2 [M+H]⁺.

Step G. Di-tert-utyl((((3aR,4R,6R,6aR)-6-(4-((2-chlorobenzyl)amino)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(17 g)

To a solution of 17f (260 mg, 0.5 mmol) in dry THF (10 mL) was addedsodium hydride (60% dispersion in mineral oil, 136 mg, 3.4 mmol) at −40°C. The mixture was stirred at −40° C. for 30 min and then a solution of(di-tert-butoxyphosphoryl)methyl trifluoromethanesulfonate (517 mg, 1.5mmol) in THF (5 mL) was added dropwise. After the mixture was stirred atrt for 1 h, AcOH (0.15 mL) was added. The mixture was concentrated invacuo to afford the title compound (17g) (360 mg, 100%) as a yellowsolid. The crude was used directly without further purification. m/z(ESI, +ve ion)=751.3 [M+H]⁺.

Step H.((((2R,3S,4R,5R)-5-(4-((2-Chlorobenzyl)amino)-6-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (17)

To a solution of 17 g (360 mg, 0.5 mmol) in1,1,1,3,3,3-hexafluoro-2-propano (10 mL) was added 6 N HCl (0.5 mL). Themixture was stirred at rt for 2 h and the neutralized by ammoniumhydroxide (pH=7). The mixture was concentrated and the residue waspurified by reverse preparative HPLC to afford the title compound (17)(60 mg, 24% for the two steps) as a trifluoroacetate. ¹H NMR (400 MHz,D₂O) δ 8.38-8.07 (m, 1H), 7.38-7.33 (m, 2H), 7.30-7.19 (m, 2H),6.25-6.21 (m, 1H), 4.24 (td, J=7.05, 1.97 Hz, 1H), 4.96 (s, 1H), 4.85(s, 1H), 4.79-4.70 (m, 3H), 4.44-3.39 (m, 1H), 4.20-4.18 (m, 1H),3.74-3.70 (m, 1H), 3.65-3.60 (m, 1H), 3.57-3.50 (m, 2H), m/z (ESI, +veion)=515.1 [M+H]³⁰.

Example 18.((((2R,3S,4R,5R)-5-(4-((3-Chlorobenzyl)amino)-6-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (18)

Step A.(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(4-((3-chlorobenzyl)amino)-6-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diylDiacetate (18a)

To a mixture of zinc cyanide (128 mg, 1.09 mmol) in dry DMF (15 mL) wasadded 3-chlorobenzyl analog of 1b (1 g, 1.81 mmol),tetrakis(triphenylphosphine)palladium (209 mg, 1.81 mmol), and TEA (220mg, 2.18 mmol). After the mixture was stirred at 100° C. under N₂ for 6h, it was cooled and diluted (EtOAc and water). The organic layer waswashed (brine), dried (Na₂SO₄), and evaporated. The residue was purifiedby flash column chromatography (SiO₂, 33% EtOAc/petroleum ether) toprovide the title compound (18a) (500 mg, 51%), m/z (ESI, +ve ion)=542.7[M+H]⁺.

Step B.((((2R,3S,4R,5R)-5-(4-((3-Chlorobenzyl)amino)-6-cyano-1H-pyrazolo[3,4-d]pyrimidin-1yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic Acid(18)

The title compound was prepared from(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4-(3-chlorobenzyl)amino)-6-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diylDiacetate (18a) by procedures similar to those described in Example 1,Steps C and D, followed by procedures in Example 17, Step G and H. ¹HNMR (400 MHz, D₂O) δ 8.12-7.91 (m, 1H), 7.24-7.17 (m, 4H), 6.10-6.25 (m,1H), 4.66-4.58 (m, 2H), 4.33-4.31 (t, J=5.0 Hz, 1H), 4.16-4.14 (m, 1H),3.68-3.56 (m, 2H), 3.41-3.28 (m, 3H), m/z (ESI, +ve ion)=511.2 [M+H]⁺.

Example 19.((((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (19)

Step A.((3aR,5R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylBenzoate (19a)

BzCl (5.91 g, 42 mmol) was added slowly to a solution of(3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(8 g, 42 mmol) in pyridine (80 mL) at 0° C. The mixture was stirred atrt for 2 h, it was concentrated and the residue was diluted with EtOAcand aq. citric acid. The organic layer was washed (brine), dried andconcentrated. The residue was purified by flash column chromatography toprovide the title compound (19a) (11 g, 89%), m/z (ESI, +ve ion)=295.4[M+H]⁺.

Step B.((3aR,5R,6aS)-2,2-Dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]diozol-5-yl)methylBenzoate (19b)

To a solution of 19a (6.5 g, 22.1 mmol) in DCM (130 ml) was added PDC (5g, 13.3 mmol) and acetic anhydride (6.76 g, 66.3 mmol) at rt. After themixture was refluxed for 2 h, it was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography to provide the title compound (19b) (4.2 g, 65% yield),m/z (ESI, +ve ion)=333.3 [M+MeCN]⁺.

Step C.((3aR,5R,6R,6aR)-6-Hydroxy-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]diozol-5-yl)methylBenzoate (19c)

To a solution of 19b (1 g, 3.4 mmol) in dry THF (20 ml) was addeddropwise MeMgBr (3 M in THF, 1.7 ml, 5.1 mmol) at 0° C. After themixture was stirred for 0.5 h, it was quenched (aq. NH₄Cl) and extracted(EtOAc). The organic layer was dried and concentrated to afford thetitle compound (19c) (1.2 g, 3.63 mmol). The crude product was used inthe next step without further purification. m/z (ESI, +ve ion)=331.4[M+H]⁺.

Step D.((2R,3S,4R,5S)-3,4,5-Trihydroxy-3-methyltetrahydrofuran-2-yl)methylBenzoate (19d)

A solution of 19c (1.2 g, 3.63 mmol) in TFA (90% in water, 10 ml) wasstirred at rt for 0.5 h. The mixture was concentrated in vacuo todryness and the residue was used in the next step without furtherpurification. m/z (ESI, +ve ion)=291.4 [M+Na]⁺.

Step E.(3R,4R,5R)-5-((Benzoyloxy)methyl)-4-methyltetrahydrofuran-2,3,4-triylTriacetate (19e)

To a solution of crude 19d prepared from above step in pyridine (20 ml)were added acetic anhydride (7 ml) and DMAP (20 mg). After the mixturewas stirred at rt overnight, it was concentrated in vacuo and theresidue was diluted with EtOAc. The solution was washed (water andbrine) and the organic layer was dried, concentrated. The residue waspurified by flash column chromatography to provide the title compound(19e) (430 mg, 32%), m/z (ESI, +ve ion)=417.4.

Step F.(2R,3R,4R,5R)-2-((Benzoylozy)methyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-methyltetrahydrofuran-3,4-diylDiacetate (19f)

To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (206 mg, 1.09mmol) and 19e (430 mg, 1.09 mmol) in MeCN (10 ml) were added TMSOTf (969mg, 4.36 mmol) and DBU (497 mg, 3.27 mmol) successively. After themixture was stirred at rt for 2 h, it was diluted (EtOAc). The organiclayer was washed (brine), dried, and concentrated. The residue waspurified by flash column chromatography to provide the title compound(191) (375 mg, 66%), m/z (EST, +ve ion)=545.4.

Step 1. ((((2R,3S,4R,5R)-5-(6-Chloro4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (19)

The title compound was prepared(2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-methyltetrahydrofuran-3,4-diyldiacetate (19f) by procedures similar to those described in Example 1,Steps B. C, and D, followed by procedure in Example 17, Step G and H. ¹HNMR (400 MHz, D₂O) δ 8.06-7.78 (m, 1H), 7.32-7.29 (m, 2H), 7.18-7.16 (m,2H), 6.02-6.00 (d, J=7.6 Hz, 1H), 4.70-4.51 (m, 3H), 4.18-4.12 (m, 1H),3.63-3.60 (m, 2H), 3.44-3.40 (m, 2H), 1.28 (s, 3H). m/z (ESI, +veion)=533.9 [M+H]⁺.

Example 20.(2-((((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isobutyl)amino)-2-oxoethyl)phosphonicAcid (20))

Step A.(3aS,4S,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carbaldehyde (20a)

Dichloroacetic acid (82 mg, 0.641 mmol) was added dropwise to a cooledsolution of((3aR,4R,6R,6aR)-6-(6-chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(1d) (600 mg, 129 mmol) and EDCl.HCl salt (850 mg) in DMSO (5 mL). Afterthe reaction mixture was stirred at rt for 3 h. it was quenched byaddition of water (15 mL) and EtOAc (15 mL). The resultant phases wereseparated and the aqueous phase was extracted (EtOAc) and the combinedorganic phases were washed (brine), dried, and concentrated to afford ayellow solid which was used in next step without purification.

Step B.6-chloro-N-(2-Chlorobenzyl)-1-((3aR,4R,6R,6aR)-6-((isobutylamino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(20b)

To a solution of 20a (600 mg, 1.3 mmol) in DCE (8 mL) was added2-methylpropan-1-amine (280 mg, 3.9 mmol) and acetic acid (332 mg, 3.9mmol). The mixture was stirred for 5 min before sodiumtriacetoxyborohydride (822 mg, 3.9 mmol) was added. After the mixturewas stirred at rt for 1 h, it was quenched (sat. NaHCO₃) and theresulting solution was stirred for 30 min. The solution was extracted(EtOAc) and the organic layer was dried (MgSO₄) and concentrated. Theresidue was purified by flash column chromatography to provide the titlecompound (20b) (310 mg, 46%), m/z (ESI, +ve ion)=520.8 [M+H]⁺.

Step C. Diethyl(2-((((3aR,4R,6R,6aR)-6-(6-Chloro-4-((2-chlorobenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)-2-oxoethyl)phosphonate(20c)

To a solution of 20b (300 mg, 0.6 mmol) and 2-(diethoxyphosphoryl)acetic acid (180 mg, 0.95 mmol) in DMF (8 ml) was added DIPEA (327 mg,2.52 mmol) and HATU (362 mg, 0.95 mmol) at 0° C. After the mixture wasstirred at rt for 1 h, it was poured into water and the solution wasextracted (EtOAc). The organic layer was dried, concentrated. Theresidue was purified by flash column chromatography to provide the titlecompound (20c) (350 mg, 87% yield), m/z (ESI, +ve ion)=699.6 [M+H]⁺.

Step D.(2-((((2R,3S,4R,5R)-5-(6-Chloro-4-((2-chlorbenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isobutyl)amino)-2-oxoethyl)phosphonicAcid (20)

TMSBr (2.63 g. 17.2 mmol) and TEA (2.32 g, 22.9 mmol) were added to asolution of 20c (350 mg. 0.5 mmol) in MeCN (20 ml) at rt. After themixture was stirred at rt overnight, it was concentrated to dryness. Theresidue was treated with 50% aq. TFA (10 ml) and the solution wasstirred for 2 h. The solution was purified by reverse preparative toprovide the title compound (20) (70 mg, 19.4% yield), m/z (ESI, +veion)=603.0 [M+H]⁺.

Example 23.((((1R,2R,3S,4R)-4-(5-Chloro-7-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyl)methoxy)methyl)phosphonicAcid (23)

Step A.((3aR,4R,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cydopenta[d][1,3]dioxol-4-yl)methanol(23a)

2,2-Dimethoxypropane (4.5 g, 43.3 mol) and para-toluenesulfonic acid(163 mg, 0.87 mmol) were added to a solution of(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl) cyclopentane-1,2-diolhydrochloride (1.59 g, 8.66 mmo) in acetone (16 ml) and the mixture wasstirred at rt overnight. After trimethylamine (2.5 ml) was added, themixture was stirred another 5 min before the solvent was removed underreduced pressure. The residue was diluted with brine and the solutionwas extracted with EtOAc. The combined organics were dried, filtered,and concentrated to afford the title compound (23a) (1.3 g, 80% yield).

Step B.((3aR,4R,6R,6aS)-6-(2,6-Dichloro-5-nitropyrimidin-4-ylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(23b)

2,4,6-Trichloro-5-nitropyrimidine (2.18 g, 9.6 mmol) and triethylamine(970 mg, 9.6 mmol) were added to a solution of 23a (1.8 g, 9.6 mmol) inTHE (20 ml) successively. After the reaction mixture was stirred at rtfor 20 min, it was diluted with EtOAc/Et₂O (1:1) and washed with 10%citric acid, brine, dried and concentrated. The residue was purified bycolumn chromatography (DCM/MeOH: from 30:1 to 10:1) to yield the titlecompound (23b) (1.6 g, 43%).

Step C.((3aR,4R,6R,6aS)-6-(5-Amino-2,6-dichloropyrimidin-1-ylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(23c)

Iron powder (1.08 g, 19.4 mmol) and acetic acid (1.16 g 19.36 mmol) wereadded to a solution of 23b (918 mg, 2.42 mmol) in ethanol (13 ml) andwater (10 ml). After the reaction mixture was heated at 60° C. for 15min, it was filtrated and the solid washed with EtOAc. The filtrate waswashed with brine and the combined organic phases were concentrated invacuo to afford the title compound (23c) (800 mg), which was used in thenext step without further purification.

Step D.((3aR,4R,6R,6aS)-6-(5,7-Dichloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(23d)

J tert-Butyl nitrite (314 mg, 2.68 mmol) was added to a solution of 23c(700 mg, 2.0 mmol) in anhydrous MeCN (20 ML) under N₂. The mixture washeated at 60° C. for 2 h and then cooled to rt, concentrated to dryness.The residue was purified by column chromatography (DCM/MeOH: from 30:1to 10:1) to give the title compound (23d) (600 mg, 83%).

Step E.((3aR,4R,6R,6aS)-6-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(23e)

A mixture of 23d (1.3 g, 3.62 mmol), (S)-2,3-dihydro-1H-inden-1-amineHCl (614 mg, 3.62 mmol), and Et₃N (438 mg, 0.919 mmol) in ethanol (30ml) was stirred at rt overnight. The mixture was concentrated and theresidue was purified by column chromatography (petroleum ether/ethylacetate=10:1 to 2:1) to give the title compound (23e) (1.2 g, 76%), m/z(ESI, +ve ion)=457.4[M−H]⁺.

Step G:((((1R,2R,3S,4R)-4-(5-chloro-7-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyl)methoxy)methyl)phosphonicAcid (23)

The title compound was prepared from((3aR,4R,6R,6aS)-6-(5-chloro-7-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(23e) by procedures similar to those described in Example 7, Steps B andC. ¹H NMR (400 MHz, D₂O) δ 7.27-7.14 (m, 4H), 5.76-5.65 (m, 1H),4.96-4.88 (m, 1H), 4.57-4.48 (m, 1H), 4.12-4.05 (m, 1H), 3.59-3.55 (m,2H), 3.43-3.38 (m, 2H), 2.98-2.96 (m, 1H), 2.88-2.84 (m, 1H), 2.54-2.35(m, 3H), 2.02-1.88 (m, 1H), 1.85-1.71 (m, 1H), m/z (ESI, +ve ion)=510.8[M+H]⁺.

The following examples were made according to the procedures describedin Examples 1-8 and 13-23 using the appropriate starting material.

Ex. LC-MS 24 520.1 [M + H]⁺ 25 510 [M − H]⁻ 26 527.2 [M + H]⁺ 27 518 [M− H]⁻ 28 635.1 [M − H]⁻ 29 501.9 [M − H]⁻ 30 520.8 [M + H]⁺ 31 525.9[M + H]⁺ 32 553.9 [M + H]⁺ 33 533.8 [M + H]⁺ 34 533.8 [M + H]⁺ 35 553.9[M + H]⁺ 36 547.9 [M + H]⁺ 37 533.8 [M + H]⁺ 38 449.9 [M + H]⁺ 39 535.1[M + H]⁺ 40 518.9 [M + H]⁺ 41 499.9 [M + H]⁺ 42 465.8 [M + H]⁺ 43 422.2[M − H]⁻ 44 497.9 [M − H]⁻ 45 479.9 [M + H]⁺ 46 508.8 [M − H]⁻ 47 552.8[M − H]⁻ 48 540.2 [M + H]⁺ 49 535.9 [M + H]⁺ 50 532 [M − H]⁻ 51 536.81[M + H]⁺ 52 409.5 [M + H]⁺ 53 477.6 [M + H]⁺ 54 557.8 [M + H]⁺ 55 555.1[M + H]⁺ 56 514.8 [M + H]⁺ 57 395.8 [M + H]⁺ 58 535.7 [M − H]⁻ 59 534.9[M + H]⁺ 60 531.7 [M − H]⁻ 61 568.0 [M + H]⁺ 62 498.0 [M + H]⁺ 63 452.3[M + H]⁺ 64 533.9 [M + H]⁺ 65 521.0 [M + H]⁺ 66 512.0 [M + H]⁺ 67 555.5[M − H]⁻ 68 461.8 [M − H]⁻ 69 480.1 [M + H]⁺ 70 479.8 [M + H]⁺ 71 479.8[M + H]⁺ 72 463.9 [M + H]⁺ 73 478 [M − H]⁻ 74 436 [M − H]⁻ 75 471.9 [M +H]⁺ 76 436.1 [M + H]⁺ 77 580.0 [M + H]⁺ 78 466.1 [M + H]⁺ 79 448 [M −H]⁻ 80 466.3 [M + H]⁺ 81 449.8 [M + H]⁺ 82 444.1 [M − H]⁻ 83 436.0 [M +H]⁺ 84 512.0 [M + H]⁺ 85 463.8 [M + H]⁺ 86 500.4 [M + H]⁺ 87 483.8 [M −H]⁻ 88 512.1 [M + H]⁺ 89 494.2 [M + H]⁺ 90 485.8 [M − H]⁻ 91 464.0 [M +H]⁺ 92 464.3 [M + H]⁺ 93 477.9 [M + H]⁺ 94 464.1 [M + H]⁺ 95 463.2 [M −H]⁻ 96 461.8 [M − H]⁻ 97 462.8 [M + H]⁺

Example 98.((N-(((2R,3S,4R,5R)-5-(6-Chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-N-methylsulfamoyl)methyl)phosphonicAcid (98)

Step A.6-Chloro-N-cyclopentyl-1-(3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(98a)

The title compound was prepared from cyclopentane analog of 1d via Swernoxidation and reductive animation successively.

Step B.N-(((3aR,4R,6R$6aR)-6-(6-Chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]diozol-4-yl)methyl)-N-methylmethanesulfonamide(98b)

To an oven dried flask was added1-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(methylaminomethyl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-N-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(98a) (156 mg, 0.37 mmol) and DCM (1.7 mL). To this solution was addedtriethylamine (0.15 mL, 1.1 mmol) and methanesulfonyl chloride (0.03 mL,0.44 mmd) at rt. The mixture was allowed to stir at rt overnight. Themixture was concentrated and the residue was purified by flash columnchromatography (0-6% MeOH/DCM) to afford the title compound (98b) (143mg, 77% yield). m/z (ESI, +ve ion)=501.1 [M+H]⁺.

Step C. tert-Butyl(6-chloro-1-(3aR,4R,6R,6aR)-2,2-dimethyl-6-((N-methylmethylsulfonamido)methyl)tetrahydrofuro[3,4-d][1,3]diozol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate(98c)

To an oven dried flask was added a solution of 98b (100 mg, 0.20 mmol)in MeCN (3 mL). To this solution was added triethylamine (0.08 mL, 0.60mmd) followed by addition of di-tert-butyl dicarbonate (0.14 mL, 0.60mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol). The mixture wasallowed to stir at rt overnight. The mixture was concentrated and theresidue was purified by flash column chromatography (0-100%EtOAc/hexanes) to give title compound (98c) (107 mg, 89% yield), m/z(ESI, +ve ion)=601.2 [M+H]⁺.

Step D.((N-(((2R,3S,4R,5R)-5-(6-Chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-N-methylsulfamoyl)methyl)phosphonicAcid (98)

The title compound was prepared from tert-butyl(6-chloro-1-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((N-methylmethylsulfonamido)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate(98c) by procedures similar to those described in Example 3, Steps B andC. m/z (ESI, +ve ion)=541.1 [M+H]⁺.

Example 99.((((2R,3S,4R,5R)-5-(6-Chloro-4-(N-cyclopentylacetamido)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (99)

Step A. Di-tert-Butyl((((3aR,4R,6R,6aR)-6-(6-chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxyl)methyl)phosphonate(99a)

The title compound was prepared from cyclopentane analog of 1d byprocedures similar to those described in Example 17, Step G.

Step B. Di-tert-butyl ((((3aR,4R,6R,6aR)-6-(6-chloro-4(N-cyclopentylacetamido)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxyl)methyl)phosphonate(99b)

Sodium hydride (60% in mineral oil, 323 mg, 8.0 mmol) was added to asolution of 99a (2 g, 4.0 mmol) in dry DMF (40 ml) at 0° C. followed bystirring for 10 min at the same temperature. Acetic anhydride (2.06 g,20 mmol) was added dropwise over ten min. The mixture was allowed towarm to rt and stirred overnight. The mixture was poured into sat.NH₄Cland extracted with EA. The organic layer was washed with water, brine,dried and concentrated in vacuo to afford the title compound (99b),which was used directed for the next step without further purification.m/z (ESI, +ve ion)=[M+Na]⁺.

Step C.((((2R,3S,4R,5R)-5-(6-Chloro-4-(N-cyclopentylacetamido)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (99)

The title compound was prepared from Di-tert-butyl((((3aR,4R,6R,6aR)-6-(6-chloro-4-(N-cyclopentylacetamido)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate(99b)) by procedures similar to those described in Example 17, Step H.m/z (ESI, +ve ion)=506.1 [M+H]⁺.

Example 100.((((2R,3S,4R,5R)-5-(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (100)

Step A.(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diylDiacetate (100a)

To a solution of 1a (6.7 g, 15 mmol) and (5-methylfuran-2-yl)boronicacid (1.91 g, 15 mmol) in THE (85 ml) were added sat. NaHCO₃ (40 ml) andPd(PPh₃)₄ (875 mg, 0.75 mmol). The mixture was flushed with N₂ and thenheated at reflux overnight. The mixture was cooled to rt and thentreated with water/EtOAc. The organic layer was washed with water,brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (PE/EA=3:1) to afford the titlecompound (100a) (4.4 g, 60% yield). m/z (EST, +ve ion)=493.1 [M+H]⁺.

Step B.((3aR,4R,6R,6aR)-6-(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(100b)

The title compound was prepared(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydrofuran-3,4-diyldiacetate (100a)) by procedures similar to those described in Example 1,Steps C and D.

Step C. ((((2R,3S,4R,5R)-5(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonicAcid (100)

The title compound was prepared((3aR,4R,6R,6aR)-6-(6-chloro-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(100b) by procedures similar to those described in Example 7, Steps Band C. ¹H NMR (400 MHz, D₂O) δ 800-7.95 (d, J=17.2 Hz, 1H), 6.91-6.87(d, J=16.0 Hz, 1H), 6.09-6.03 (m, 2H), 4.44-4.41 (t, J=4.80 Hz, 1H),4.17 (m, 1H), 3.77-3.59 (m, 4H), 2.22-2.21 (d, J=4.8 Hz, 3H), m/z (ESI,+ve ion)=461.2 [M+H]⁺.

Example 101.(3-((2R,3S,4R,5R)-5-(6-Chloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)propyl)phosphonicAcid (101)

Step A. Diethyl((E)-3-(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)alkyl)phosphonate(101a)

An oven dried 3-neck flask with reflux condenser was purged with argonand addedbenzylidene(dichloro)(1,3-dimesityl-2-imidazolidinylidene)ruthenium-tricyclohexylphosphine(1:1, 290 mg, 0.34 mmol) and DCM (8 mL). To the mixture was added(3aR,4R⁶R,6aR)-4-methoxy-2,2-dimethyl-6-vinyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole(1.94 g, 9.69 mmol) in DCM (1 mL), followed by addition of a solution ofdiethyl alkylphosphonate (2.5 g. 14.0 mmol) in DCM (1 mL) all at once.After the solution was stirred at reflux for 18 h, it was concentratedand the residue was purified by flash column chromatography (0-100%EtOAc/hexanes followed by 0-10% MeOH/DCM) to give the title compound(101a) (1.81 g, 53% yield) as a yellow oil.

Step B(3-((2R,3S,4R,5R)-5-(6-(Cloro-4-(cyclopentylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)propyl)phosphonicAcid (101)

The title compound was prepared diethyl((E)-3-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)alkyl)phosphonate(101a) by procedures similar to those described in Example 4, Steps C-H.NMR (400 MHz, 1320) S 8.15-7.99 (m, 1H), 6.01 (m, 1H), 5.17-4.96 (m,3H), 4.32-4.18 (m, 2H), 4.12-3.98 (m, 1H), 2.08-1.88 (m, 2H), 1.64-1.29(m, 10H), m/z (ESI, +ve ion)=462.1 [M+H]⁺.

The following examples were made according to the procedures describedin Examples 1-8, 13-23, 98-101 using the appropriate starting material.

Ex. LC-MS 102 491.8 [M + H]⁺ 103 491.9 [M + H]⁺ 104 477.7 [M + H]⁺ 105477.8 [M + H]⁺ 106 543 [M + H]⁺ 107 496.1 [M − H]⁻ 108 513.2 [M + H]⁺109 505 [M + H]⁺ 110 498.8 [M + H]⁺ 111 512.4 [M + H]⁺ 112 512 [M + H]⁺113 513 [M + H]⁺ 114 567.2 [M + H]⁺ 115 506.2 [M + H]⁺ 116 566.1 [M +H]⁺ 117 552.1 [M + H]⁺ 118 566.9 [M − H]⁻ 119 553.2 [M + H]⁺ 120 567.2[M − H]⁻ 121 561.2 [M + H]⁺ 122 569.1 [M + H]⁺ 123 558 [M − H]⁻ 124475.8 [M − H]⁻ 125 508.1 [M + H]⁺ 126 560.3 [M + H]⁺ 127 568.3 [M + H]⁺128 526.2 [M + H]⁺ 129 582.2 [M + H]⁺ 130 560.8 [M + H]⁺ 131 662 [M +H]⁺ 132 487.8 [M + H]⁺ 133 570 [M + H]⁺ 134 524.1 [M − H]⁻ 135 524.1 [M− H]⁻ 136 560.2 [M + H]⁺ 137 462.9 [M + H]⁺ 138 473.2 [M − H]⁻

II. Biological Evaluation Example A1: Biochemical Assay Assay ReactionConditions

-   -   Assay Volume: 70 μl    -   Reaction Volume: 50 μl    -   CD73: 0.3208 nM    -   AMP: 15 μM    -   Assay Buffer: 2 5 mM Tris-HCL, pH 7.4, 0.01% Brij-35, 0.01% BSA,        5 mM MgCl₂

Assay Procedure;

Used 384 clear plate.

Made dose titration of testing compounds in assay buffer, 10 points ½log titrations in duplicates starting at 100 μM.

Added 25 μl of CD73 to each well for a final concentration of 320 pM.

Incubated at RT for 15 min.

Added 25 μl of AMP to each well for a final concentration of 15 μM.

Incubated at RT for 10 min.

Added 10 μl of Malachite Green Reagent A, incubate at RT for 10 min.

Added 10 μl of Malachite Green Reagent B, incubate at RT for 45 min.

Read the Absorbance on Envision plate reader using excitation filter:Cy5 620 nM.

The ability of the compounds disclosed herein to inhibit CD73 activitywas quantified and the respective IC₅₀ values were determined. Table 1provides the biochemical IC₅₀ values of compounds disclosed herein.

Ex. Biochemical IC₅₀ Ex. Biochemical IC₅₀ Ex Biochenlica IC₅₀  1 A 48 A 93 A  2 C 49 A  94 A  3 A 50 C  95 A  4 C 51 A  96 A  5 C 52 A  97 C  6C 53 A  98 A  7 A 54 C  99 A  8 B 55 C 100 A  9 A 56 C 101 B 10 A 57 B102 A 11 C 58 A 103 A 12 A 59 A 104 A 13 A 60 C 105 A 14 A 61 A 106 A 15A 62 A 107 A 16 A 63 A 108 A 17 A 64 B 109 A 18 A 65 C 110 A 19 B 66 A111 A 20 C 67 C 112 A 23 A 68 A 113 A 24 A 69 A 114 A 25 A 70 p 115 B 26B 71 p 116 A 27 A 72 A 117 A 28 C 73 A 118 A 29 A 74 A 119 A 30 A 75 A120 A 31 A 76 A 121 A 32 A 77 A 122 A 33 A 78 A 123 A 34 A 79 A 124 A 35A 80 A 125 A 36 C 81 A 126 A 37 A 82 B 127 A 38 A 83 A 128 A 39 A 84 A129 A 40 A 85 C 130 A 41 A 86 A 132 C 42 A 87 A 133 A 43 A 88 C 134 A 44C 89 A 135 A 45 A 90 B 136 A 46 A 91 A 137 A 47 A 92 A 138 A A: IC₅₀ ≤500 nM; B: 500 nM < IC₅₀ ≤ 1 μM C: 1 μM < IC₅₀

What is claimed is:
 1. A compound of Formula (IIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein; A is —O— or —CH₂—; Q¹ is CW and Q² is N; or Q¹ is N and Q² isN; W is hydrogen, halogen, —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a),—NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b),—C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d),—NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R³⁰; Z is —NR¹R², —OR⁶⁰,—SR⁶¹, or —CR⁶²R⁶³R⁶⁴; R¹ and R² are each independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(═O)₂R^(15a),—S(═O)₂NR^(16a)R^(17a), or —C(═)₂R^(15a), wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30a); orR¹ and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b); R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),—C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30m); R⁶¹ is hydrogen,—C(═O)R^(15f), —C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30n); R⁶², R⁶³, andR⁶⁴ are each independently hydrogen, halogen, —CN, —OH, —OR^(15g), —SH,—SR^(15g), —S(═O)R^(15g), —NO₂, —NR^(16g)R^(17g), —S(═O)₂R^(15g),—NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),—C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),—OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),—NR^(16g)C(═O)R^(15g), —NR^(16g)C(O)OR^(16g), C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30o); R³ is halogen,—CN, —OH, —OR^(15b), —SR^(18b), —NR^(18b)R^(17b), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30c); R⁴ and R⁷ areeach independently hydrogen, halogen, —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(13c), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30d); R⁵ and R⁶ are eachindependently hydrogen, halogen, —OH, —OR^(15d), —NR^(16c)S(═O)₂R^(15d),—NR^(16d)C(═O)R^(15d), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30e); X¹is a bond; Y¹ is —S(═O)₂—; Y² is —(CR⁴⁵R⁴⁶)_(v2)—; R⁴⁵ and R⁴⁶ are eachindependently hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆ haloalkyl; v2 is 1-3; R^(15a), R^(15b), R^(15c),R^(15d), R^(15e), R^(15f), R^(15g) are each independently C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30g); R^(16a), R^(16b), R^(16c),R^(16d), R^(16e), R^(16f), R^(16g), R^(17a), R^(17b), R^(17e), R^(17f),and R^(17g) are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three R^(30h); or R^(16a) andR^(17a) or R^(16b) and R^(17b) or R^(16e) and R^(17c) or R^(16f) andR^(17f) or R^(16g) and R^(17g) are taken together with the nitrogen atomto which they are attached to form a heterocycloalkyl optionallysubstituted with one, two, or three halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; R^(18b) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30h); R²¹ and R²² areeach independently hydrogen, C₁-C₂₀alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),—(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,—(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30k); orR²¹ and R²² are taken together with the atoms to which they are attachedto form a heterocycloalkyl optionally substituted with one, two, orthree R^(30l); each R²³ and R²⁴ are independently hydrogen, halogen,—OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R²⁵ isindependently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, orC₁-C₆ heteroalkyl; each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl; each w is independently 1-4; eachR³⁰, R^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R^(30g), R^(30h),R^(30i), R^(30j), R^(30k), R^(30l), R^(30m), R^(30n), and R^(30o) areindependently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a),—NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b), —OC(O)OR^(b), —C(O)NR^(c)R^(d),—OC(O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),—NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R³¹; each R³¹ isindependently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a), —S(═O)R^(a),—NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),—C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b), —OC(O)OR^(b),—C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), —NR^(b)C(O)NR^(c)R^(d),—NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b), C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, or cycloalkyl optionallysubstituted with one, two, or three halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; each R^(a) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three halogen, —OH, C₁-C₆alkyl, or C₁-C₆ haloalkyl; each R^(b) is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one, two, or three halogen,—OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R^(c) and R^(d) are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; whereinthe alkyl, alkenyl, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is independently optionally substituted with one,two, or three halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; or R^(c)and R^(d) are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.
 2. The compoundof claim 1, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen,or C₁-C₆ alkyl; and v2 is 1 or
 2. 3. The compound of claim 1 or 2,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴⁵ and R⁴⁶ are each hydrogen; and v2 is
 1. 4. The compound ofany one of claims 1-3, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; Q¹ is CW; and Q² is N.
 5. The compound ofany one of claims 1-3 pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; Q¹ is N; and Q² is N.
 6. The compound ofany one of claims 1-4, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; W is hydrogen, halogen, —CN, —OH,—OR^(a), —NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl, is independently optionally substituted with one, two,or three R³⁰.
 7. The compound of any one of claims 1-4 or 6,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; W is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₄alkyl, or C₁-C₆ haloalkyl.
 8. The compound of any one of claims 1-4 or 6or 7, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; W is hydrogen.
 9. The compound of any one of claims1-8, pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; A is —O—.
 10. The compound of any one of claims 1-8,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; A is —CH₂—.
 11. The compound of any one of claims 1-10,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₆alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30e).
 12. The compoundof any one of claims 1-11, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; each R^(30e) is independently halogen orC₁-C₆ alkyl.
 13. The compound of any one of claims 1-12,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁵ and R⁶ are each hydrogen.
 14. The compound of any one ofclaims 1-13, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R⁴ and R⁷ are each independently hydrogen, halogen,—OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30d).15. The compound of any one of claims 1-14, pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; each R^(30d) isindependently halogen or C₁-C₆ alkyl.
 16. The compound of any one ofclaims 1-15, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R⁴ and R⁷ are each independently hydrogen, halogen,—OH, —OR^(15c), —NR^(16c)S(═O)₂R^(15c), or —NR^(16c)C(═O)R^(15c). 17.The compound of any one of claims 1-16, pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R^(15c) and R^(15d) areeach independently C₁-C₆ alkyl or C₁-C₆ haloalkyl; and R^(16c) andR^(16d) are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl.
 18. The compound of any one of claims 1-17, pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R^(15c) andR^(15d) are each independently C₁-C₆ alkyl; and R^(16c) and R^(16d) areeach independently hydrogen or C₁-C₆ alkyl.
 19. The compound of any oneof claims 1-18, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁴ and R⁷ are each independentlyhydrogen, halogen, or —OH.
 20. The compound of any one of claims 1-19,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴ and R⁷ are each independently halogen or —OH.
 21. Thecompound of any one of claims 1-20, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R⁴ and R⁷ are each —OH. 22.The compound of any one of claims 1-21, pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; Z is —NR¹R².
 23. Thecompound of any of claims 1-22, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl), —S(═O)₂R^(15a), —S(═O)₂NR^(16a)R^(17a), or—C(═O)₂R^(15a); wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30a).
 24. The compound of any ofclaims 1-23, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R^(15a) is C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl);wherein each alkyl and aryl is optionally substituted with one, two, orthree halogen; and R^(15a) and R^(17a) are each independently hydrogen,C₁-C₆ alkyl, aryl, or C₁-C₆ alkyl(aryl); wherein each alkyl and aryl isoptionally substituted with one, two, or three halogen; and
 25. Thecompound of any of claims 1-24, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl; andR^(16a) and R^(17a) are each independently hydrogen or C₁-C₆ alkyl. 26.The compound of any one of claims 1-25, pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl,cycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a).
 27. The compoundof any one of claims 1-26, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independentlyoptionally substituted with one, two, or three R^(30a).
 28. The compoundof any one of claims 1-27, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R¹ is cycloalkyl or C₁-C₆ alkyl(aryl);wherein each alkyl, cycloalkyl, and aryl is independently optionallysubstituted with one, two, or three R^(30a).
 29. The compound of any oneof claims 1-28, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; each R^(30a) is independently halogen,—CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optimally substituted with one, two, or three R³¹.
 30. Thecompound of any one of claims 1-29, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; each R³¹ is independentlyhalogen or C₁-C₆ alkyl.
 31. The compound of any one of claims 1-30,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl.
 32. The compound of any one of claims 1-31,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30a) is independently halogen.
 33. The compound of anyone of claims 1-32, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R² is hydrogen or C₁-C₆ alkyl.
 34. Thecompound of any one of claims 1-25, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R¹ and R² are taken togetherwith the nitrogen atom to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(31b).35. The compound of any one of claims 1-25 or 34, pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R¹ and R²are taken together with the nitrogen atom to which they are attached toform a piperidine or a pyrrolidine optionally substituted with one, two,or three R^(30b).
 36. The compound of any one of claims 1-25 or 34 or35, pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30b) is independently aryl optionally substituted withone, two, or three R³¹; and each R³¹ is independently halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl.
 37. The compound of any one of claims 1-25 or34-36, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R^(30b) is aryl.
 38. The compound of any one of claims1-37, pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R³ is halogen, —CN, —SR^(18b), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c).
 39. The compound of any oneof claims 1-38, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R³ is halogen, —CN, —SR^(18b), C₁-C₆alkyl, or C₁-C₆ alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl isindependently optionally substituted with one, two, or three R^(30c).40. The compound of any one of claims 1-39, pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R^(18b) is cycloalkylor C₁-C₆ alkyl(cycloalkyl).
 41. The compound of any one of claims 1-40,pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30c) is independently halogen or C₁-C₆ alkyl.
 42. Thecompound of any one of claims 1-38, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R³ is halogen.
 43. Thecompound of any one of claims 1-42, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R²¹ and R²² are eachindependently hydrogen, aryl, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵.
 44. Thecompound of any one of claims 1-43, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R²¹ and R²² are eachhydrogen.
 45. The compound of claim 1, pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from:


46. A compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof:

wherein; Q³ and Q⁴ are independently N or CW¹; provided that at leastone of Q³ or Q⁴ is N; W¹ is hydrogen, halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl; A is —O— or —CH₂—; Z is —NR¹R², —OR⁶⁰, —SR⁶¹,or —CR⁶²R⁶³R⁶⁴; R¹ and R² are each independently hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl), —S(═O)₂R^(15a),—S(═O)₂NR^(16a)R^(17a), or —C(═O)₂R^(15a); wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30a); orR¹ and R² are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one,two, or three R^(30b); R⁶⁰ is hydrogen, —C(═O)R^(15e), —C(═O)OR^(16e),—C(═O)NR^(16e)R^(17e), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30m); R⁶¹ is hydrogen,—C(═O)R^(15f), —C(═O)OR^(16f), —C(═O)NR^(16f)R^(17f), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl),C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30n); R⁶², R⁶³, andR⁶⁴ are each independently hydrogen, halogen, —CN, —OH, —OR^(15g), —SH,—SR^(15g), —S(═O)R^(15g), —NO₂, —NR^(16g)R^(17g), —S(═O)₂R^(15g),—NHS(═O)₂R^(15g), —S(═O)₂NR^(16g)R^(17g), —C(═O)R^(15g), —OC(═O)R^(15g),—C(═O)OR^(16g), —OC(═O)OR^(16g), —C(═O)NR^(16g)R^(17g),—OC(═O)NR^(16g)R^(17g), —NR^(16g)C(═O)NR^(16g)R^(17g),—NR^(16g)C(═O)R^(15g), —NR^(16g)C(═O)OR^(16g), C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30o); R³is halogen, —CN, —OH, —OR^(15b), —SR^(18b), —NR^(16b)R^(17b), C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30c); R⁴and R⁷ are each independently hydrogen, halogen, —OH, —OR^(15c),—NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30d); R⁵ and R⁶ are eachindependently hydrogen, halogen, —OH, —OR^(15d), —NR^(16d)S(═O)₂R^(15d),—NR^(16d)C(═O)R^(15d), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30e); R⁸is hydrogen, halogen, —OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆haloalkyl; R⁹ and R¹⁰ are each independently hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl; X¹ is bond, —C(═O)—, —S(═O)₂—, —O—, or—CR⁴⁰R⁴¹—; Y¹ is —C(═O)—, —(CR⁴²R⁴³)_(v1)—, —S(═O)₂—, —NR⁴⁴—, —S—, or—O—; Y¹ is —(CR⁴⁵R⁴⁶)_(v2)—, —NR⁴⁷— or —O—; R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁵, andR⁴⁶ are each independently hydrogen, halogen, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one, two,or three R^(30f); R⁴⁴ and R⁴⁷ are each independently hydrogen,—S(═O)R^(a), —S(═O)—R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one, two,or three R^(30f); v1 and v2 are each independently 1-3; R^(15a),R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g) are eachindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30g);R^(16a), R^(16b), R^(16c), R^(16d), R^(16e), R^(16f), R^(16g)A, R^(17a),R^(17b), R^(17e), R^(17f), and R^(17g) are each independently hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one, two,or three R^(30h); or R^(16a) and R^(17a) or R^(16b) and R^(17b) orR^(16e) and R^(17e) or R^(16f) and R^(17f) or R^(16g) and R^(17g) aretaken together with the nitrogen atom to which they are attached to forma heterocycloalkyl optionally substituted with one, two, or threehalogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(18b) is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), orC₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30i); R²¹ and R²² areeach independently hydrogen, C₁-C₂₀alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), C₁-C₆ alkyl(heterocycloalkyl),—(CR²³R²⁴)_(w)C(═O)OR²⁵, —(CR²³R²⁴)_(w)OC(═O)R²⁶,—(CR²³R²⁴)_(w)SC(═O)R²⁶, or —(CR²³R²⁴)_(w)OC(═O)OR²⁵; wherein eachalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R^(30k); orR²¹ and R²² are taken together with the atoms to which they are attachedto form a heterocycloalkyl optionally substituted with one, two, orthree R^(30l); each R²³ and R¹⁴ are independently hydrogen, halogen,—OH, —OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R²⁵ isindependently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, orC₁-C₆ heteroalkyl; each R²⁶ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, or C₁-C₆ heteroalkyl; each w is independently 1-4; eachR^(30a), R^(30b), R^(30c), R^(30d), R^(30e), R_(30f), R^(30g), R^(30h),R^(30i), R^(30j), R^(30k), R^(30l), R^(30m), R^(30n), R^(30o), andR^(30p) are independently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),—S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a),—S(═O)₃NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),—OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one, two, or three R³¹; eachR³¹ is independently halogen, —CN, —OH, —OR^(a), —SH, —SR^(a),—S(═O)R^(a), —NO₂, —NR^(c)R^(d), —S(═O)₂R^(a), —NHS(═O)₂R^(a),—S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),—OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(O)R^(a), —NR^(b)C(O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, orcycloalkyl optimally substituted with one, two, or three halogen, C₁-C₆alkyl, or C₁-C₄ haloalkyl; each R^(a) is independently C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optimally substituted with one, two, or three halogen,—OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R^(b) is independentlyhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R^(c) and R^(d)are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three halogen, —OH, C₁-C₆alkyl, or C₁-C₆ haloalkyl; or R^(c) and R^(d) are taken together withthe nitrogen atom to which they are attached to form a heterocycloalkyloptionally substituted with one, two, or three halogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl.
 47. The compound of claim 46, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein:


48. The compound of claim 46 or 47, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein:


49. The compound of any one of claims 46-48, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein:


50. The compound of any one of claims 46-48, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein:


51. The compound of any one of claims 46-50, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; Q³ is N andQ⁴ is CW¹.
 52. The compound of any one of claims 46-50, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; Q⁴ is N and Q³ is CW¹.
 53. The compound of any one of claims46-50, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; Q³ is N and Q⁴ is N.
 54. The compound of any one ofclaims 46-53, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; W¹ is hydrogen, halogen, or C₁-C₆ alkyl.55. The compound of any one of claims 46-54, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁸ ishydrogen or C₁-C₆ alkyl.
 56. The compound of any one of claims 46-55, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁸ is hydrogen.
 57. The compound of any one of claims 46-56, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁹ and R¹⁰ are each independently hydrogen or C₁-C₆ alkyl. 58.The compound of any one of claims 46-57, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁹ and R¹⁰are each hydrogen.
 59. The compound of any one of claims 46-58, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴⁰ and R⁴¹ are each independently hydrogen, halogen, —OH,—OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, or C₁-C₆ haloalkyl.
 60. The compoundof any one of claims 46-59, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R⁴⁰ and R⁴¹ are eachindependently hydrogen, halogen, —OH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.61. The compound of any one of claims 46-60, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁴⁰ and R⁴¹are each hydrogen.
 62. The compound of any one of claims 46-61, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴² and R⁴³ are each independently hydrogen, halogen, —OH,—OR^(a), or C₁-C₆ alkyl.
 63. The compound of any one of claims 46-62, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴² and R⁴³ are each hydrogen.
 64. The compound of any one ofclaims 46-63, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁴⁴ is hydrogen, —S(═O)R^(a),—C(═O)R^(a), C₁-C₆ alkyl, C₁-C₆ haloalkcyl, or C₁-C₆ alkyl(aryl). 65.The compound of any one of claims 46-64, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁴⁴ ishydrogen or C₁-C₆ alkyl.
 66. The compound of any one of claims 46-65, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, —OH,—OR^(a), —NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one, two, or three R^(30p).
 67. The compoundof any one of claims 46-66, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R⁴⁵ and R⁴⁶ are eachindependently hydrogen, halogen, C₁-C₆ alkyl, or cycloalkyl; whereineach alkyl and cycloalkyl is independently optionally substituted withone, two, or three R^(30p).
 68. The compound of any one of claims 46-67,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴⁵ and R⁴⁶ are each independently hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkyl(cycloalkyl),C₁-C₆ alkyl(aryl), or cycloalkyl.
 69. The compound of any one of claims46-68, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R⁴⁵ and R⁴⁶ are each independently hydrogen or C₁-C₆alkyl.
 70. The compound of any one of claims 46-69, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴⁵ and R⁴⁶ are each hydrogen.
 71. The compound of any one ofclaims 46-67, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁴⁵ is halogen, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl isindependently optionally substituted with one, two, or three R^(30p);and R⁴⁶ is hydrogen or C₁-C₆ alkyl.
 72. The compound of any one ofclaims 46-67 or 71, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁴⁵ is halogen, C₁-C₆ alkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one, two, or three R^(30p); and R⁴⁶ ishydrogen or C₁-C₆ alkyl.
 73. The compound of any one of claims 46-67 or71 or 72, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁴⁵ is halogen, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(aryl), or cycloalkyl; and R⁴⁶ is hydrogen or C₁-C₆ alkyl.
 74. Thecompound of any one of claims 46-67 or 71-73, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁴⁵ is C₁-C₆alkyl; and R⁴⁶ is hydrogen or C₁-C₆ alkyl.
 75. The compound of any oneof claims 46-74, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; A is —O—.
 76. The compound of any one ofclaims 46-74, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; A is —CH₂—.
 77. The compound of any oneof claims 46-76, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R⁵ and R⁶ are each independentlyhydrogen, halogen, C₁-C₆ alkyl, or cycloalkyl; wherein each alkyl andcycloalkyl is independently optionally substituted with one, two, orthree R^(30e).
 78. The compound of any one of claims 46-77, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30c) is independently halogen or C₁-C₆ alkyl.
 79. Thecompound of any one of claims 46-78, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R⁵ and R⁶ are eachhydrogen.
 80. The compound of any one of claims 46-79, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴ and R⁷ are each independently hydrogen, halogen, —OH,—OR^(15c), —NR^(16c)S(═O)₂R^(15c), —NR^(16c)C(═O)R^(15c), C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30d).
 81. The compoundof any one of claims 46-80, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; each R^(30d) is independentlyhalogen or C₁-C₆ alkyl.
 82. The compound of any one of claims 46-80, ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴ and R⁷ are each independently hydrogen, halogen, —OH,—OR^(15c), —NR^(16c)S(═O)₂R^(15e), or —NR^(16c)C(═O)R^(15e).
 83. Thecompound of any one of claims 46-82, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R^(15c) and R^(15d) areeach independently C₁-C₆ alkyl or C₁-C₆ haloalkyl; and R^(16c) andR^(16d) are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl.
 84. The compound of any one of claims 46-83, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R^(15c) and R^(15d) are each independently C₁-C₆ alkyl; andR^(16c) and R^(16d) are each independently hydrogen or C₁-C₆ alkyl. 85.The compound of any one of claims 46-84, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R⁴ and R⁷are each independently hydrogen, halogen, or —OH.
 86. The compound ofany one of claims 46-85, or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein; R⁴ and R⁷ are each independentlyhalogen or —OH.
 87. The compound of any one of claims 46-86, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R⁴ and R⁷ are each —OH.
 88. The compound of any one of claims46-87, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; Z is —NR¹R².
 89. The compound of any one of claims46-88, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; R¹ is C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆ alkyl(heteroaryl), C₁-C₆alkyl(cycloalkyl), or C₁-C₆ alkyl(heterocycloalkyl); wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one, two, or three R^(30a).
 90. The compoundof any one of claims 46-89, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl,cycloalkyl, heterocycloalkyl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30a).
 91. The compound of any oneof claims 46-90, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R¹ is C₁-C₆ alkyl, cycloalkyl, or C₁-C₆alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independentlyoptionally substituted with one, two, or three R^(30a).
 92. The compoundof any one of claims 46-91, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R¹ is cycloalkyl or C₁-C₆alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independentlyoptionally substituted with one, two, or three R^(30a).
 93. The compoundof any one of claims 46-92, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; each R^(30a) is independentlyhalogen, —CN, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one, two, orthree R³¹.
 94. The compound of any one of claims 46-93, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30a) is independently halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, or C₁-C₆ haloalkyl.
 95. The compound of any one of claims 46-94,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; each R^(30a) is independently halogen.
 96. The compound of anyone of claims 46-95, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R² is hydrogen or C₁-C₆ alkyl.
 97. Thecompound of any one of claims 46-88, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein; R¹ and R² are takentogether with the nitrogen atom to which they are attached to form aheterocycloalkyl optionally substituted with one, two, or three R^(30b).98. The compound of any one of claims 46-88 or 97, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein; R¹ and R²are taken together with the nitrogen atom to which they are attached toform an azetidine, a piperidine, a morpholine, or a pyrrolidineoptionally substituted with one, two, or three R^(30b).
 99. The compoundof any one of claims 46-98, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R³ is halogen, —CN,—OR^(15b), —SR^(18b), —NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆ alkyl(aryl), C₁-C₆alkyl(heteroaryl), C₁-C₆ alkyl(cycloalkyl), or C₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one, two, or three R^(30c).
 100. The compound of anyone of claims 46-99, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R³ is halogen, —CN, —OR^(15b),—NR^(16b)R^(17b), C₁-C₆ alkyl, cycloalkyl, or heterocycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one, two, or three R^(30c).
 101. The compound of anyone of claims 46-100, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R^(15b) is C₁-C₆ alkyl.
 102. The compoundof any one of claims 46-101, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein; R^(16b) and R^(17b) areindependently hydrogen or is C₁-C₆ alkyl.
 103. The compound of any oneof claims 46-102, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; each R^(30c) is independently halogen orC₁-C₆ alkyl.
 104. The compound of any one of claims 46-103, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R³ is halogen.
 105. The compound of any one of claims 46-104,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R²¹ and R²² are each independently hydrogen, aryl, or—(CR²³R²⁴)_(w)OC(═O)OR²⁵.
 106. The compound of any one of claims 46-105,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein; R²¹ and R²² are each hydrogen.
 107. The compound of any one ofclaims 46-106, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R²¹ and R²² are taken together with theatoms to which they are attached to form a heterocycloalkyl optionallysubstituted with one, two, or three R^(30l).
 108. The compound of anyone of claims 46-107, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R^(30l) is C₁-C₆ alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optimallysubstituted with one, two, or three R³¹.
 109. The compound of any one ofclaims 46-108, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein; R^(30l) is aryl optionally substitutedwith one, two, or three R³¹.
 110. The compound of any one of claims46-109, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein; each R³¹ is independently halogen or C₁-C₆ alkyl. 111.The compound of claim 46, pharmaceutically acceptable salt, solvate, orstereoisomer thereof, selected from:


112. A pharmaceutical composition comprising a compound of any one ofclaims 1-111, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and a pharmaceutically acceptable excipient. 113.A method of inhibiting CD73 comprising contacting CD73 with a compoundof any one of claims 1-111, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof.
 114. A method of treating cancer in asubject, comprising administering to the subject a compound of any oneof claims 1-111, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.
 115. A method of treating cancer in a subject,comprising administering to the subject a pharmaceutical composition ofclaim
 112. 116. The method of either of claim 114 or 115, wherein thecancer is lung cancer, melanoma, breast cancer, ovarian cancer,colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer,renal cancer, or a lymphoma.
 117. The method of any one of claims113-116, further comprising administering a second therapeutic agent.118. The method of claim 117, wherein the second therapeutic agent is achemotherapeutic agent or an immunotherapy agent.
 119. A method oftreating an infection in a subject, comprising administering to thesubject a compound of any one of claims 1-111, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof.
 120. A method oftreating an infection in a subject, comprising administering to thesubject a pharmaceutical composition of claim
 112. 121. The method ofeither of claim 119 or 120, wherein the infection is a viral infection.122. The method of either of claim 119 or 120, wherein the infection isa parasitic infection.
 123. A method of treating a neurodegenerativedisease in a subject, comprising administering to the subject a compoundof any one of claims 1-111, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof.
 124. A method of treating aneurodegenerative disease in a subject, comprising administering to thesubject a pharmaceutical composition of claim
 112. 125. The method ofeither of claim 123 or 124, wherein the neurodegenerative disease isAlzheimer's disease, Parkinson's disease, Huntington's disease,schizophrenia, or autism.